Quinoxaline carboxamide derivatives as protein tyrosine kinase inhibitors

ABSTRACT

The invention relates to compounds of formula (I) 
     
       
         
         
             
             
         
       
     
     wherein the substituents are as defined in the specification, in free form or in the form of a pharmaceutically acceptable salt, solvate, ester, N-oxide thereof; processes for the preparation thereof; to pharmaceuticals containing such compounds, in particular for the use in one or more Protein tyrosine kinase mediated diseases.

This application claims priority to EP Application Serial No. 08156846.1filed 23 May 2008, the contents of which are incorporated herein byreference in their entirety.

FIELD OF THE INVENTION

The invention relates to quinoline/quinoxaline-carboxamide derivativesof the formula (I) given below (including its salts, solvates, esters,N-oxides); processes for the preparation thereof; pharmaceuticalcompositions comprising a compound of the formula (I), optionally in thepresence of a combination partner; the application of a compound offormula (I) in a process for the treatment of the human or animal body,(in particular with regard to a proliferative disease); the use of acompound of formula (I) for manufacturing a medicament for the treatmentof such diseases.

BACKGROUND OF THE INVENTION

Protein kinases (PKs) are enzymes which catalyze the phosphorylation ofspecific serine, threonine or tyrosine residues in cellular proteins.These post-translational modifications of substrate proteins act asmolecular switch regulating cell proliferation, activation and/ordifferentiation. Aberrant or excessive PK activity has been observed inmany disease states including benign and malignant proliferativedisorders. In many cases, it has been possible to treat diseases invitro and in many cases in vivo, such as proliferative disorders, bymaking use of PK inhibitors. The kinases fall largely into two groups,those specific for phosphorylating serine and threonine, and thosespecific for phosphorylating tyrosine. In addition, some kinases,referred to as “dual specificity” kinases, are able to phosphorylatetyrosine as well as serine/threonine residues.

WO2006/000420 (in particular p. 1-8) discloses details on PKs, theirmode of action and relation to disorders or conditions to be treated.This document also discloses heteroaryl aryl ureas, useful for thetreatment of protein kinase dependent diseases. Further, WO03/023004 andWO02/102972 disclose disorders resulting from FGFR3 mutations. Further,WO05/118580 generically discloses quinoline derivatives useful as HIVinhibitors. In these documents and the references cited therein, whereprotein kinases are involved, the modulation of an aberrant activity(especially the inhibition of an activity of such a kinase) can beexpected reasonably to be useful in the diseases mentioned in thisdocument.

Although considered active, the molecules disclosed in theabove-referenced documents; they show certain disadvantages. There isthus an unmet need for improved (e.g. highly affine and/or selective)molecules capable of blocking aberrant constitutive receptor proteintyrosine kinase activity, in particular FGFR activity, therebyaddressing the clinical manifestations associated with theabove-mentioned mutations, and modulating various biological functions.In view of the large number of protein kinase inhibitors and themultitude of proliferative and other PK-related diseases, there is anever-existing need to provide novel classes of compounds that are usefulas PK inhibitors and thus in the treatment of these Protein TyrosineKinase (PTK) related diseases. Particularly required are new classes ofpharmaceutically advantageous PK inhibiting compounds.

DETAILED DESCRIPTION OF THE INVENTION

Thus, in a first aspect, the invention relates to compounds of theformula (I),

wherein

-   X represents N or CH;-   R¹ represents    -   hydrogen,    -   halogen,    -   alkyl,    -   alkyl substituted with saturated heterocyclyl which is        unsubstituted or substituted by alkyl,    -   amino,    -   mono-substituted amino wherein the substituent is selected from        the group consisting of alkyl, aminoalkyl, alkylaminoalkyl,        dialkylaminoalkyl,    -   di-substituted amino wherein the substituents are selected from        the group consisting of alkyl, aminoalkyl, alkylaminoalkyl,        dialkylaminoalkyl,    -   alkoxy,    -   substituted alkoxy wherein the substituents are selected from        the group consisting of halo and alkoxy;-   R² represents    -   hydrogen,    -   halogen,    -   alkyl,    -   alkyl substituted with saturated heterocyclyl which is        unsubstituted or substituted by alkyl,    -   amino,    -   mono-substituted amino wherein the substituent is selected from        the group consisting of alkyl, aminoalkyl, alkylaminoalkyl,        dialkylaminoalkyl,    -   di-substituted amino wherein the substituents are selected from        the group consisting of alkyl, aminoalkyl, alkylaminoalkyl,        dialkylaminoalkyl,    -   alkoxy,    -   substituted alkoxy wherein the substituents are selected from        the group consisting of halo and alkoxy;-   A represents aryl or heteroaryl;-   B represents aryl or heteroaryl;-   R^(A1) represents hydrogen or a substituent different from hydrogen;-   R^(A2) represents a direct bond or an alkanediyl;-   R^(B1) represents hydrogen or a substituent different from hydrogen;-   R^(B2) represents a direct bond or aminocarbonyl;-   m represents an integer selected from 0 to 3;-   n represents an integer selected from 0 to 5;-   or a salt, solvate, ester, N-oxide thereof.

The invention may be more fully appreciated by reference to thefollowing description, including the following glossary of terms and theconcluding examples. As used herein, the terms “including”, “containing”and “comprising” are used herein in their open, non-limiting sense.

Any formula given herein is intended to represent compounds havingstructures depicted by the structural formula as well as certainvariations or forms. In particular, compounds of any formula givenherein may have asymmetric centers and therefore exist in differentenantiomeric forms. If at least one asymmetrical carbon atom is presentin a compound of the formula (I), such a compound may exist in opticallyactive form or in the form of a mixture of optical isomers, e.g. in theform of a racemic mixture. All optical isomers and their mixtures,including the racemic mixtures, are part of the present invention. Thus,any given formula given herein is intended to represent a racemate, oneor more enantiomeric forms, one or more diastereomeric forms, andmixtures thereof. Furthermore, certain structures may exist as geometricisomers (i.e. cis and trans isomers), as tautomers, or as atropisomers.Additionally, any formula given herein is intended to representhydrates, solvates, and polymorphs of such compounds, and mixturesthereof.

Any formula given herein is also intended to represent unlabeled formsas well as isotopically labeled forms of the compounds. Isotopicallylabeled compounds have structures depicted by the formulas given hereinexcept that one or more atoms are replaced by an atom having a selectedatomic mass or mass number. Examples of isotopes that can beincorporated into compounds of the invention include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine,such as ³H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸F, ³¹P, ³²P, ³⁵S, ³⁶Cl ¹²⁵Irespectively. Various isotopically labeled compounds of the presentinvention, for example those into which radioactive isotopes such as ³H,¹³C, and ¹⁴C are incorporated. Such isotopically labelled compounds areuseful in metabolic studies (preferably with ¹⁴C), reaction kineticstudies (with, for example ²H or ³H), detection or imaging techniquessuch as positron emission tomography (PET) or single-photon emissioncomputed tomography (SPECT) including drug or substrate tissuedistribution assays, or in radioactive treatment of patients. Inparticular, an ¹⁸F or labeled compound may be particularly preferred forPET or SPECT studies. Further, substitution with heavier isotopes suchas deuterium (i.e., ²H) may afford certain therapeutic advantagesresulting from greater metabolic stability, for example increased invivo half-life or reduced dosage requirements. Isotopically labeledcompounds of this invention and prodrugs thereof can generally beprepared by carrying out the procedures disclosed in the schemes or inthe examples and preparations described below by substituting a readilyavailable isotopically labeled reagent for a non-isotopically labeledreagent.

When referring to any formula given herein, the selection of aparticular moiety from a list of possible species for a specifiedvariable is not intended to define the moiety for the variable appearingelsewhere. In other words, where a variable appears more than once, thechoice of the species from a specified list is independent of the choiceof the species for the same variable elsewhere in the formula (where oneor more up to all more general expressions in embodiments characterizedas preferred above or below can be replaced with a more specificdefinition, thus leading to a more preferred embodiment of theinvention, respectively).

It goes without saying that substituents are only at positions wherethey are chemically possible, the person skilled in the art being ableto decide (either experimentally or theoretically) without inappropriateeffort which substitutions are possible and which are not. For example,amino or hydroxy groups with free hydrogen may be unstable if bound tocarbon atoms with unsaturated (e.g. olefinic) bonds. Additionally, itwill of course be understood that the substituents as listed above maythemselves be substituted by any substituent, subject to theaforementioned restriction to appropriate substitutions as recognised bythe skilled man.

Where the plural form (e.g. compounds, salts) is used, this includes thesingular (e.g. a single compound, a single salt). “A compound” does notexclude that (e.g. in a pharmaceutical formulation) more than onecompound of the formula (I) (or a salt thereof) is present.

The acid addition salt of compounds of formula (I) are preferablypharmaceutically acceptable salts. Such salts are known in the field.

The following general definitions shall apply in this specification,unless otherwise specified:

Halogen (or halo) denotes fluorine, bromine, chlorine or iodine, inparticular fluorine, chlorine. Halogen-substituted groups and moieties,such as alkyl substituted by halogen (halogenalkyl) can be mono-, poly-or per-halogenated.

Heteroatoms are atoms other than Carbon and Hydrogen, preferablynitrogen (N), oxygen (O) or sulfur (S).

The prefix “lower” or “C₁-C₇” denotes a radical having up to andincluding a maximum of 7, especially up to and including a maximum of 4carbon atoms, the radicals in question being either linear or branchedwith single or multiple branching.

“Alkyl” refers to a straight-chain or branched-chain alkyl group,preferably represents a straight-chain or branched-chain C₁₋₁₂alkyl,particularly preferably represents a straight-chain or branched-chainC₁₋₇alkyl; for example, methyl, ethyl, n- or iso-propyl, n-, iso-, sec-or tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl,n-undecyl, n-dodecyl, with particular preference given to methyl, ethyl,n-propyl, iso-propyl and n-butyl and iso-butyl. Alkyl may beunsubstituted or substituted. Exemplary substituents include, but arenot limited to hydroxyl, alkoxy, halogen and amino. An example of asubstituted alkyl is trifluoromethyl. Cycloalkyl may also be asubstituent to alkyl. An example of such a case is the moiety(alkyl)-cyclopropyl or alkanediyl-cycloproyl, e.g. —CH₂-cyclopropyl.C₁-C₇-alkyl is preferably alkyl with from and including 1 up to andincluding 7, preferably from and including 1 to and including 4, and islinear or branched; preferably, lower alkyl is butyl, such as n-butyl,sec-butyl, isobutyl, tert-butyl, propyl, such as n-propyl or isopropyl,ethyl or preferably methyl.

Each alkyl part of other groups like “alkoxy”, “alkoxyalkyl”,“alkoxycarbonyl”, “alkoxycarbonylalkyl”, “alkylsulfonyl”,“alkylsulfinyl”, “alkylamino”, “halogenalkyl” shall have the samemeaning as described in the above-mentioned definition of “alkyl”.

“Alkanediyl” refers to a straight-chain or branched-chain alkanediylgroup. It preferably represents a straight-chain or branched-chain C₁₋₁₂alkanediyl, particularly preferably represents a straight-chain orbranched-chain C₁₋₆ alkanediyl; for example, methandiyl (—CH₂—),1,2-ethanediyl (—CH₂—CH₂—), 1,1-ethanediyl ((—CH(CH₃)—), 1,1-, 1,2-,1,3-propanediyl and 1,1-, 1,2-, 1,3-, 1,4-butanediyl, with particularpreference given to methandiyl, 1,1-ethanediyl, 1,2-ethanediyl,1,3-propanediyl, 1,4-butanediyl. Alkanediyl may be substituted orunsubstituted as defined for alkyl, preferably unsubstituted.

“Cycloalkyl” refers to a saturated or partially saturated, monocyclic,fused polycyclic, or spiro polycyclic, carbocycle having from 3 to 12ring atoms per carbocycle. Illustrative examples of cycloalkyl groupsinclude the following moieties: cyclopropyl, cyclobutyl, cyclpentyl andcylclohexyl. Cycloalkyl may be unsubstituted or substituted; exemplarysubstituents are provided in the definition for alkyl.

“Aryl” refers to an aromatic homocyclic ring system with 6 or morecarbon atoms; aryl is preferably an aromatic moiety with 6 to 14 ringcarbon atoms, more preferably with 6 to 10 ring carbon atoms, such asphenyl or naphthyl, preferably phenyl. Aryl may be unsubstituted orsubstituted by one or more, preferably up to three, more preferably upto two substituents independently selected from the group consisting ofunsubstituted or substituted heterocyclyl as described below, especiallypyrrolidinyl, such as pyrrolidino, oxopyrrolidinyl, such asoxo-pyrrolidino, C₁-C₇-alkyl-pyrrolidinyl,2,5-di-(C₁-C₇alkyl)pyrrolidinyl, such as2,5-di-(C₁-C₇alkyl)-pyrrolidino, tetrahydrofuranyl, thiophenyl,C₁-C₇-alkylpyrazolidinyl, pyridinyl, C₁-C₇-alkylpiperidinyl, piperidino,piperidino substituted by amino or N-mono- or N,N-di-[lower alkyl,phenyl, C₁-C₇-alkanoyl and/or phenyl-lower alkyl)-amino, unsubstitutedor N-lower alkyl substituted piperidinyl bound via a ring carbon atom,piperazino, lower alkylpiperazino, morpholino, thiomorpholino,S-oxo-thiomorpholino or S,S-dioxothiomorpholino; C₁-C₇-alkylamino-C₁-C₇alkyl, N—C₁-C₇-alkanoylamino-C₁-C₇-alkyl,N—C₁-C₇-alkanesulfonyl-amino-C₁-C₇-alkyl, carbamoyl-C₁-C₇-alkyl,[N-mono- or N,N-di-(C₁-C₇-alkyl)-carbamoyl]C₁-C₇-alkyl,C₁-C₇-alkanesulfinyl-C₁-C₇-alkyl, C₁-C₇alkanesulfonyl-C₁-C₇-alkyl,phenyl, naphthyl, mono- to tri-[C₁-C₇-alkyl, halo and/or cyano]-phenylor mono- to tri-[C₁-C₇-alkyl, halo and/or cyano]-naphthyl;C₃-C₈-cycloalkyl, mono- to tri-[C₁-C₇-alkyl and/orhydroxy]-C₃-C₈-cycloalkyl; halo, hydroxy, lower alkoxy,lower-alkoxy-lower alkoxy, (lower-alkoxy)-lower alkoxy-lower alkoxy,halo-C₁-C₇-alkoxy, phenoxy, naphthyloxy, phenyl- or naphthyl-loweralkoxy; amino-C₁-C₇-alkoxy, lower-alkanoyloxy, benzoyloxy, naphthoyloxy,formyl (CHO), amino, N-mono- or N,N-di-(C₁-C₇-alkyl)-amino,C₁-C₇-alkanoylamino, C₁-C₇-alkanesulfonylamino, carboxy, lower alkoxycarbonyl, e.g.; phenyl- or naphthyl-lower alkoxycarbonyl, such asbenzyloxycarbonyl; C₁-C₇-alkanoyl, such as acetyl, benzoyl, naphthoyl,carbamoyl, N-mono- or N,N-disubstituted carbamoyl, such as N-mono- orN,N-di-substituted carbamoyl wherein the substitutents are selected fromlower alkyl, (lower-alkoxy)-lower alkyl and hydroxy-lower alkyl;amidino, guanidino, ureido, mercapto, lower alkylthio, phenyl- ornaphthylthio, phenyl- or naphthyl-lower alkylthio, loweralkyl-phenylthio, lower alkyl-naphthylthio, halogen-lower alkylmercapto,sulfo (—SO₃H), lower alkanesulfonyl, phenyl- or naphthyl-sulfonyl,phenyl- or naphthyl-lower alkylsulfonyl, alkylphenylsulfonyl,halogen-lower alkylsulfonyl, such as trifluoromethanesulfonyl;sulfonamido, benzosulfonamido, azido, azido-C₁-C₇-alkyl, especiallyazidomethyl, C₁-C₇-alkanesulfonyl, sulfamoyl, N-mono- orN,N-di-(C₁-C₇-alkyl)-sulfamoyl, morpholinosulfonyl,thiomorpholinosulfonyl, cyano and nitro; where each phenyl or naphthyl(also in phenoxy or naphthoxy) mentioned above as substituent or part ofa substituent of substituted alkyl (or also of substituted aryl,heterocyclyl etc. mentioned herein) is itself unsubstituted orsubstituted by one or more, e.g. up to three, preferably 1 or 2,substituents independently selected from halo, halo-lower alkyl, such astrifluoromethyl, hydroxy, lower alkoxy, azido, amino, N-mono- orN,N-di-(lower alkyl and/or C₁-C₇-alkanoyl)-amino, nitro, carboxy,lower-alkoxycarbonyl, carbamoyl, cyano and/or sulfamoyl.

“Heterocyclyl” refers to a heterocyclic radical that is unsaturated(=carrying the highest possible number of conjugated double bonds in thering(s)), saturated or partially saturated and is preferably amonocyclic or in a broader aspect of the invention bicyclic, tricyclicor spirocyclic ring; and has 3 to 24, more preferably 4 to 16, mostpreferably 5 to 10 and most preferably 5 or 6 ring atoms; the bondingring preferably having 4 to 12, especially 5 to 7 ring atoms. Theheterocyclic radical (heterocyclyl) may be unsubstituted or substitutedby one or more, especially 1 to 3, substituents independently selectedfrom the group consisting of the substituents defined above forsubstituted alkyl and/or from one or more of the following substituents:oxo (═O), thio (═S), imino(═NH), imino-lower alkyl. Further,heterocyclyl is especially a heterocyclyl radical selected from thegroup consisting of oxiranyl, azetidine, azirinyl, aziridinyl,1,2-oxathiolanyl, thienyl (=thiophenyl), furanyl, tetrahydrofuryl,pyranyl, thiopyranyl, thianthrenyl, isobenzofuranyl, benzofuranyl,chromenyl, 2H-pyrrolyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl,imidazolidinyl, benzimidazolyl, pyrazolyl, pyrazinyl, pyrazolidinyl,thiazolyl, isothiazolyl, dithiazolyl, oxazolyl, isoxazolyl, pyridyl,pyrazinyl, pyrimidinyl, piperidinyl, piperazinyl, pyridazinyl,morpholinyl, thiomorpholinyl, (S-oxo or S,S-dioxo)-thiomorpholinyl,indolizinyl, azepanyl, diazepanyl, especially 1,4-diazepanyl,isoindolyl, 3H-indolyl, indolyl, benzimidazolyl, cumaryl, indazolyl,triazolyl, tetrazolyl, purinyl, 4H-quinolizinyl, isoquinolyl, quinolyl,tetrahydroquinolyl, tetrahydroisoquinolyl, decahydroquinolyl,octahydroisoquinolyl, benzofuranyl, dibenzofuranyl, benzothiophenyl,dibenzothiophenyl, phthalazinyl, naphthyridinyl, quinoxalyl,quinazolinyl, quinazolinyl, cinnolinyl, pteridinyl, carbazolyl,beta-carbolinyl, phenanthridinyl, acridinyl, perimidinyl,phenanthrolinyl, furazanyl, phenazinyl, phenothiazinyl, phenoxazinyl,chromenyl, isochromanyl, chromanyl, benzo[1,3]dioxol-5-yl and2,3-dihydro-benzo[1,4]dioxin-6-yl, each of these radicals beingunsubstituted or substituted by one or more, preferably up to three,substituents selected from those mentioned above for substituted aryland/or from one or more of the following substituents: oxo (═O), thio(═S), imino(═NH), imino-lower alkyl.

“Heteroaryl” refers to a specific subgroup of heterocyclyl, namely suchunsaturated heterocyclic groups that are also aromatic. Such heteroarylmay be substituted with substituents as identified above forheterocyclyl. Further, heteroaryl may be a charged moiety, such as inpyridine-N-oxide. Due to tautomerism, e.g. keto-enol-tautomerism,heteroaryl may also be drawn as a partly unsaturated heterocyclyl (e.g.2-hydroxypyridine). For example, heteroaryl includes pyridyl,pyrimidinyl, pyridazinyl, 1,3,5-triazolyl, 1,2,3-triazolyl,1,2,4-triazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, acridinyl,purinyl, pteridinyl, pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl,1,2,4-triazolyl, indolyl, indazolyl, benzopyranyl, benzothiopyranyl,benzo[1,3]dioxole, benzo-imidazolyl, tetrazolyl, furanyl, benzofuranyl,oxazolyl, isoxazolyl, thienyl, thiazolyl, isothiazolyl, etc.

“Arylalkyl” refers to an aryl group bound to the molecule via an alkylgroup, such as a methyl or ethyl group, preferably phenethyl or benzyl,in particular benzyl. Similarly, cycloalkylalkyl and heterocyclylrepresents a cycloalkyl group bound to the molecule via an alkyl groupor a heterocyclyl group bound to the molecule via an alkyl group. Ineach instance, aryl, heterocyclyl, cycloalkyl and alkyl may besubstituted as defined above.

“Treatment” includes prophylactic (preventive) and therapeutic treatmentas well as the delay of progression of a disease or disorter.

“FGFR kinase mediated diseases” (especially FGFR3 kinase mediateddiseases) are such diseases, disorders or conditions (collectively“diseases”) that respond in a beneficial way, e.g. amelioration of oneor more symptoms, delay of the onset of a disease, up to temporary orcomplete cure from a disease, to the inhibition of a protein tyrosinekinase, especially inhibition of a FGFR (such as FGFR3) kinase. Amongthe diseases to be treated by FGFR inhibition, especially proliferativediseases such as cancer diseases, solid tumors like breast cancer,bladder cancer, endometrial cancer, hepatocellular cancer, glioblastoma,or multiple myeloma, EMS myeloid proliferative disorders, may bementioned.

“Salts” (which, what is meant by “or salts thereof” or “or a saltthereof”, can be present alone or in mixture with free compound of theformula (I) are preferably pharmaceutically acceptable salts. Such saltsare formed, for example, as acid addition salts, preferably with organicor inorganic acids, from compounds of formula (I) with a basic nitrogenatom, especially the pharmaceutically acceptable salts. Suitableinorganic acids are, for example, halogen acids, such as hydrochloricacid, sulfuric acid, or phosphoric acid. Suitable organic acids are,e.g., carboxylic acids or sulfonic acids, such as fumaric acid ormethansulfonic acid. For isolation or purification purposes it is alsopossible to use pharmaceutically unacceptable salts, for examplepicrates or perchlorates. For therapeutic use, only pharmaceuticallyacceptable salts or free compounds are employed (where applicable in theform of pharmaceutical preparations), and these are therefore preferred.In view of the close relationship between the novel compounds in freeform and those in the form of their salts, including those salts thatcan be used as intermediates, for example in the purification oridentification of the novel compounds, any reference to the freecompounds hereinbefore and hereinafter is to be understood as referringalso to the corresponding salts, as appropriate and expedient.

Combination refers to either a fixed combination in one dosage unitform, or a kit of parts for the combined administration where a compoundof the formula (I) and a combination partner (e.g. an other drug asexplained below, also referred to as “therapeutic agent” or “co-agent”)may be administered independently at the same time or separately withintime intervals, especially where these time intervals allow that thecombination partners show a cooperative, e.g. synergistic effect. Theterms “co-administration” or “combined administration” or the like asutilized herein are meant to encompass administration of the selectedcombination partner to a single subject in need thereof (e.g. apatient), and are intended to include treatment regimens in which theagents are not necessarily administered by the same route ofadministration or at the same time. The term “pharmaceuticalcombination” as used herein means a product that results from the mixingor combining of more than one active ingredient and includes both fixedand non-fixed combinations of the active ingredients. The term “fixedcombination” means that the active ingredients, e.g. a compound offormula (I) and a combination partner, are both administered to apatient simultaneously in the form of a single entity or dosage. Theterm “non-fixed combination” means that the active ingredients, e.g. acompound of formula (I) and a combination partner, are both administeredto a patient as separate entities either simultaneously, concurrently orsequentially with no specific time limits, wherein such administrationprovides therapeutically effective levels of the two compounds in thebody of the patient. The latter also applies to cocktail therapy, e.g.the administration of three or more active ingredients.

In preferred embodiments, which are preferred independently,collectively or in any combination or sub-combination, the inventionrelates to a compound of the formula (I), in free base form or in acidaddition salt form, wherein the substituents are as defined herein.

In another embodiment, the invention relates to a compound of formula IA

wherein the substituents are as defined for a compound of formula I.

In a further embodiment, the invention relates to a compound of formulaIB

wherein the substituents are as defined for a compound of formula I.

In a further embodiment, the invention relates to a compound of formulaIC

wherein the substituents are as defined for a compound of formula I.

In a further embodiment, the invention relates to a compound of formulaID

wherein the substituents are as defined for a compound of formula I.

In a further embodiment, the invention relates to a compound of formulaIE

wherein the substituents are as defined for a compound of formula I.

In a further embodiment, the invention relates to a compound of formulaIF

wherein the substituents are as defined for a compound of formula I.

In a further embodiment, the invention relates to a compound of formulaIG

wherein the substituents are as defined for a compound of formula I.

In a further embodiment, the invention relates to a compound of formulaIH

wherein the substituents are as defined for a compound of formula I.

The below mentioned preferences for the substituents may apply in anycombination or subcombination to the compounds of formulae IA to IH.

-   R¹ preferably represents    -   hydrogen,    -   halogen,    -   substituted C₁₋₁₂alkyl wherein the substitutents are selected        from the group of saturated, mono-, bi-, tri- or spirocyclic        heterocyclyl having 5 to 10 ring atoms and which heterocyclyl is        unsubstituted or substituted by C₁₋₁₂alkyl,    -   amino,    -   mono-substituted amino wherein the substituent is selected from        the group consisting of C₁₋₁₂alkyl, amino C₁₋₁₂alkyl,    -   di-substituted amino wherein the substituents are selected from        the group consisting of C₁₋₁₂alkyl, amino C₁₋₁₂alkyl,    -   C₁₋₁₂alkoxy,    -   halo-C₁₋₁₂alkoxy.-   R¹ particular preferably represents    -   hydrogen,    -   fluoro,    -   chloro,    -   C₁₋₄alkyl,    -   substituted C₁₋₄alkyl wherein the substitutents are selected        from the group of saturated, monocyclic heterocyclyl having 5 to        6 ring atoms and which heterocyclyl is unsubstituted or        substituted by C₁₋₄alkyl,    -   amino,    -   mono-substituted amino wherein the substituent is selected from        the group consisting of C₁₋₄alkyl,    -   di-substituted amino wherein the substituents are selected from        the group consisting of C₁₋₁₄alkyl, amino-C₁₋₁₄alkyl,        di-C₁₋₁₄alkyl-amino C₁₋₁₄alkyl, C₁₋₄alkoxy,    -   fluoro-C₁₋₁₄alkoxy,

chloro-C₁₋₁₄alkoxy.

-   R¹ very particular preferably represents hydrogen,    (2-dimethylamino-ethyl)-methyl-amino, 4-ethyl-piperazin-1-ylmethyl,    methyl; with particular preference given to hydrogen.-   R² preferably represents    -   hydrogen,    -   halogen,    -   C₁₋₁₂alkyl    -   substituted C₁₋₁₂alkyl wherein the substitutents are selected        from the group of saturated, mono-, bi-, tri- or spirocyclic        heterocyclyl having 5 to 10 ring atoms and which heterocyclyl is        unsubstituted or substituted by C₁₋₁₂alkyl,    -   amino,    -   mono-substituted amino wherein the substituent is selected from        the group consisting of C₁₋₁₂alkyl, amino C₁₋₁₂alkyl,        C₁₋₁₂alkyl-amino-C₁₋₁₂alkyl, di-C₁₋₁₂alkyl-amino-C₁₋₁₂alkyl,    -   di-substituted amino wherein the substituents are selected from        the group consisting of C₁₋₁₂alkyl, amino C₁₋₁₂alkyl,        C₁₋₁₂alkyl-amino-C₁₋₁₂alkyl, di-C₁₋₁₂alkyl-amino C₁₋₁₂alkyl,    -   C₁₋₁₂alkoxy,    -   halo-C₁₋₁₂alkoxy.-   R² particular preferably represents    -   hydrogen,    -   fluoro,    -   chloro,    -   C₁₋₄alkyl,    -   substituted C₁₋₁₄alkyl wherein the substitutents are selected        from the group of saturated, monocyclic heterocyclyl having 5 to        6 ring atoms and which heterocyclyl is unsubstituted or        substituted by C₁₋₁₄alkyl),    -   amino,    -   mono-substituted amino wherein the substituent is selected from        the group consisting of C₁₋₁₄alkyl, amino-C₁₋₁₂alkyl,        C₁₋₁₂alkyl-amino-C₁₋₁₂alkyl, di-C₁₋₁₂alkyl-amino C₁₋₁₂alkyl,    -   di-substituted amino wherein the substituents are selected from        the group consisting of C₁₋₁₄alkyl, amino-C₁₋₁₂alkyl,        C₁₋₁₂alkyl-amino-C₁₋₁₂alkyl, di-C₁₋₁₂alkyl-amino C₁₋₁₂alkyl,    -   C₁₋₄alkoxy,    -   fluoro-C₁₋₁₄alkoxy,    -   chloro-C₁₋₁₄alkoxy.-   R² very particular preferably represents hydrogen,    (2-dimethylamino-ethyl)-methyl-amino, 4-ethyl-piperazin-1-yl-methyl,    methyl; with particular preference given to hydrogen.-   A preferably represents an aromatic moiety with 6 to 14 ring carbon    atoms or a heteroaromatic moiety with 5-13 ring; whereby such    aromatic or heteroaromatic moiety is unsubstituted or substituted by    one or more substituents —R^(A1)—R^(A2) as defined herein.-   A particular preferably represents an aromatic moiety selected from    the group consisting of phenyl, naphtyl or a heteroaromatic moiety    with 5 to 6 ring atoms and whereby at least one of the heteroatoms    is nitrogen, each aromatic or heteroaromatic moiety is unsubstituted    or substituted by one or more substituents —R^(A1)—R^(A2) as defined    herein.-   A very particular preferably represents optionally substituted aryl    or heteroaryl wherein said aryl or heteroaryl is selected from the    group consisting of phenyl, pyridyl (such as pyrid-2-yl,    pyrid-3-yl), pyrimidyl (such as pyramid-5-yl), pyrolyl (such as    pyrol-3-yl), imidazolyl (such as imidazo-2-yl or imidazo-4-yl),    pyrazolyl (such as pyradzo-3-yl), triazolyl (such as triazo-3-yl)    and wherein said aryl or heteroaryl is unsubstituted or substituted    by one or more substituents —R^(A1)—R^(A2) as defined herein.-   B preferably represents an aromatic moiety with 6 to 14 ring carbon    atoms or a heteroaromatic moiety with 5-13 ring atoms; whereby such    aromatic or heteroaromatic moiety is unsubstituted or substituted by    one or more substituents —R^(B1)—R^(B2) as defined below.-   B particular preferably represents an aromatic moiety selected from    the group consisting of phenyl, naphtyl or a heteroaromatic moiety    with 5 to 10 ring atoms and whereby at least one of the heteroatoms    is nitrogen or sulfur, each aromatic or heteroaromatic moiety is    unsubstituted or substituted by one or more substituents    —R^(B1)—R^(B2) as defined herein.-   B very particular preferably represents optionally substituted aryl    or heteroaryl wherein said aryl or heteroaryl is selected from the    group consisting of phenyl, naphthyl (such as alpha-naphtyl),    pyridyl (such as pyrid-3-yl), pyridyl-N-oxide (such as    pyrid-3-yl-N-oxide), chinolinyl, isochinolinyl (such as    isochinolin-4-yl, isochinolin-5-yl), thiophenyl (such as    thiophen-3-yl), thionaphthenyl (such as thionaphthen-3-yl) and    wherein said aryl or heteroaryl is unsubstituted or substituted by    one or more substituents —R^(B1)—R^(B2) as defined herein.-   R^(A1) preferably represents hydrogen; or formyl, C₁₋₇alkylcarbonyl,    C₁₋₇alkoxycarbonyl, aminocarbonyl, N—C₁₋₇alkylaminocarbonyl,    N,N-di-C₁₋₇alkylaminocarbonyl; benzyl; or hydroxy, C₁₋₇alkoxy,    amino-C₁₋₇alkoxy, C₁₋₇alkoxy, N,N-di-C₁₋₇alkylamino-C₁₋₇alkoxy;    heterocyclyl-C₁₋₇alkoxy whereby said heterocyclyl has 3 to 10 ring    atoms, at least one ring atom is nitrogen, is bound via nitrogen, is    optionally substituted by C₁₋₇alkyl and/or hydroxy; or a group    —NR^(A3)R^(A4) or a group —C(O)—NR^(A3)R^(A4).-   R^(A1) particular preferably represents hydrogen; or formyl,    C₁₋₄alkylcarbonyl, C₁₋₄alkoxycarbonyl, aminocarbonyl,    N,N-di-C₁₋₁₄alkylaminocarbonyl; benzyl; or hydroxy, C₁₋₄alkoxy,    N,N-di-C₁₋₄alkylamino-C₁₋₄alkoxy; heterocyclyl-C₁₋₄alkoxy whereby    said heterocyclyl has 5 to 6 ring atoms, at least one ring atom is    nitrogen, is bound via nitrogen, is optionally substituted by    C₁₋₄alkyl; or a group —NR^(A3)R^(A4).-   R^(A1) very particular preferably represents hydrogen; or    methoxycarbonyl, tert.butoxycarbonyl, aminocarbonyl; or a group    —NR^(A3)R^(A4); or hydroxy, N,N-dimethylaminoethoxy,    N,N-dimethylaminomethoxy; heterocyclyl-C₁₋₄alkoxy whereby said    heterocyclyl is bound via nitrogen and selected from the group    consisting of pyrrolidinyl, piperidinyl, N-methylpiperazinyl,    N-ethyl-piperazinyl, N-isopropyl-piperazinyl or morpholinyl.-   R^(A2) preferably represents a direct bond or a straight-chain or    branched-chain C₁₋₁₂ alkanediyl.-   R^(A2) particular preferably represents a direct bond or a    straight-chain or branched-chain C₁₋₆ alkanediyl.-   R^(A2) very particular preferably represents a direct bond,    methandiyl, 1,2-ethanediyl, 1,1-ethanediyl, 1,1-, 1,2-,    1,3-propanediyl and 1,1-, 1,2-, 1,3-, 1,4-butanediyl, with    particular preference given to direct bond, methandiyl,    1,2-ethanediyl.-   R^(A3) and R^(A4) preferably represent independent from each other    hydrogen, C₁₋₇alkyl, hydroxy-C₁₋₇alkyl, halogen-C₁₋₇alkyl,    cyano-C₁₋₇alkyl, amino-C₁₋₇alkyl, N—C₁₋₇alkylamino-C₁₋₇alkyl,    N,N-di-C₁₋₇alkylamino-C₁₋₇alkyl, aminocarbonyl-C₁₋₇alkyl,    N—C₁₋₇alkylaminocarbonyl-C₁₋₇-alkyl,    N,N-di-C₁₋₇alkylaminocarbonyl-C₁₋₇-alkyl, a saturated, partly    saturated or unsaturated hetereocycle which has 3 to 10 ring atoms,    and which is optionally substituted by 1 to 3 substituents selected    from the group consisting of C₁₋₇alkyl, hydroxyl, oxo,    hydroxy-C₁₋₇alkyl, benzyl, methoxybenzyl, amino, C₁₋₇alkylamino,    N,N-di-C₁₋₇alkylamino or-   R^(A3) and R^(A4) preferably represent together with the nitrogen to    which they are bound a saturated, partly saturated or unsaturated    hetereocycle which has 3 to 10 ring atoms, and which is optionally    substituted by 1 to 3 substituents selected from the group    consisting of C₁₋₇alkyl, cyano, halogen, hydroxyl, oxo,    hydroxy-C₁₋₇alkyl, C₁₋₇alkylcarbonyl, benzyl, methoxybenzyl, amino,    C₁₋₇alkylamino,-   R^(A3) and R^(A4) particular preferably represent independent from    each other methyl, ethyl, n- or iso-propyl, n-, iso-, sec- or    tert-butyl, hydroxymethyl, 2-hydroxyethyl, amino-methyl or -ethyl,    dimethylaminomethyl or -ethyl, aminocarbonyl-methyl or -ethyl,    N,N-dimethylaminocarbonyl-methyl or -ethyl,    N,N-diethylaminocarbonyl-methyl or -ethyl or-   R^(A3) and R^(A4) particular preferably represent together with the    nitrogen to which they are bound a saturated, partly saturated or    unsaturated hetereocycle selected from the group consisting of    azetidine, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl,    thiomorpholinyl, and which is optionally substituted by 1    substituent selected from the group consisting of methyl, ethyl, n-    or iso-propyl, n-, iso-, sec- or tert-butyl, cyano, halogen,    hydroxy, oxo, hydroxyethyl, benzyl, methoxybenzyl,    N,N-dimethylamino, N,N-diethylamino.-   R^(B1) preferably represents halo, a straight-chain or    branched-chain unsubstituted C₁₋₇alkyl, a straight-chain or    branched-chain unsubstituted C₁₋₇alkoxy, straight-chain or    branched-chain halo-C₁₋₇alkyl.-   R^(B1) particular preferably represents methyl, ethyl, n- or    iso-propyl, n-, iso-, sec- or tert-butyl, n-pentyl, n-hexyl,    n-heptyl, methyoxy, ethyoxy, n- or iso-propoxy, n-, iso-, sec- or    tert-butoxy, n-pentoxy, n-hexoxy, n-heptoxy, fluormethyl,    chlormethyl, trifluoromethyl, fluoro, chloro, bromo.-   R^(B1) very particular preferably represents methyl, methoxy,    trifluormethyl, fluoro, chloro.-   R^(B2) preferably represents a direct bond.-   m preferably represents 0, 1, 2, 3 or 4.-   m particular preferably represents 0, 1 or 4.-   n preferably represents 0, 1 or 2-   n particular preferably represents 0 or 1.

In a further embodiment when ring B represents phenyl and n represents2, the substituents R^(B2)—R^(B1) are preferably in the ortho-positions.

In a further embodiment when ring B represents phenyl and n represents4, the substituents R^(B2)—R^(B1) are preferably in the ortho andmeta-positions.

The invention further relates to pharmaceutically acceptable prodrugs ofa compound of formula (I).

The invention further relates to pharmaceutically acceptable metabolitesof a compound of formula (I).

The invention further relates to protected derivatives of a compound offormula (I).

The invention relates especially to the compounds of the formula (I)given in the Examples, as well as the methods of manufacture describedtherein.

The invention also provides, in a second aspect, pharmacological uses ofcompounds of formula (I). The compounds of formula (I) have valuablepharmacological properties, as described hereinbefore and hereinafter.They inhibit various protein kinases, such as tyrosine kinases, forexample VEGFR2 (KDR), PDGFR, cKIT, LCK, cAbl, RET and FGFR kinases,especially FGFR1, FGFR2, FGFR3, FGFR4.

In Vitro Experiments

The efficacy of the compounds of formula (I) as inhibitors of proteinkinase activity can be demonstrated according to known procedures; inparticular according to the assays described in the experimental partbelow. Generally, the activity of a protein kinase is assayed in thepresence or absence of inhibitor by measuring the phosphorylation of asynthetic substrate by purified N-terminally His- or GST-tagged kinasedomains, in the presence of selected concentrations of ATP and using theappropriate assay technology: Time-Resolved Fluorescence ResonanceEnergy Transfer (TR-FRET) (LanthaScreen™) or microfluidic Calipersystem.

In Vivo Experiments

There are also experiments to demonstrate the antitumor activity ofcompounds of the formula (I) in vivo according to methods known in thefield (e.g. as described herein).

The in vivo antitumor activity is tested, for example, using bladdercarcinoma cell lines, such as the human urinary bladder transitionalcell carcinoma RT112 cell line (DSMZ ACC #418).

Tumors are obtained after subcutaneous injection of the respective cells(minimum 1×10⁶ cells in 100 ml phosphate buffered physiological saline)into the carrier mice or rat. The treatment is started, as soon as thetumor has reached an average size of 100 mm³. Tumor growth is determinedthree times weekly and 24 h after the last treatment by measurement ofthe perpendicular diameter. In case of tumors, tumor volumes aredetermined according to the Formula L×D×p/6 (see Evans, B. D., Smith, I.E., Shorthouse, A. J. and Millar, J. J., Brit. J. Cancer, 45: 466-468,1982). The antitumor activity is expressed as T/C % (average increase ofthe tumor volume of treated animals divided by the average increase oftumor volume in control animals multiplied by 100). Tumor regression (%)represents the smallest mean tumor volume compared to the mean tumorvolume at the beginning of the treatment. Each animal in which the tumorreaches a diameter of more than 1.5 to 2 cm³ is sacrificed.

Clinical Studies

The pharmacological activity of a compound of formula (I) may, forexample, be demonstrated in a clinical study or in a test procedureaccording to methods generally accepted in the field; e.g. asessentially described hereinafter.

Suitable clinical studies are, for example, open label non-randomized,dose escalation studies in patients with one of the tumor diseasesmentioned above. The beneficial effects on proliferative diseases can bedetermined directly through the results of these studies or by changesin the study design which are known as such to a person skilled in theart. The efficacy of the treatment can be determined in such studies,e.g., in case of tumors after 18 or 24 weeks by radiologic evaluation ofthe tumors every 6 weeks, in case of a leukemia e.g. by determination ofthe count of aberrant white blood cells, and by staining mononuclearcells and/or by means of determining minimum residual disease (MRD) e.g.by FACS-LPC MRD or PCR.

Alternatively, a placebo-controlled, double blind study can be used inorder to prove the benefits of the compounds of the formula (I)mentioned herein.

An exemplary (though not limiting) schedule for administration of acompound of formula (I) is daily administration, with preferably 1 to 3daily dosages for a longer time, possibly until the disease is cured or,if only palliative treatment is achieved, for as long as required;alternatively, treatment e.g. for 5 days, and/or administration at days1, 4 and 9, with eventual repetition after a certain time withouttreatment is possible. Alternatively, treatment several times a day(e.g. 2 to 5 times) or treatment by continuous administration (e.g.infusion), e.g. at the time points indicated in the last sentence, arepossible. Generally, administration is orally or parenterally,preferably orally. The test compounds are preferably diluted in water orin sterile 0.9% saline.

Diseases:

On the basis of these tests and studies, a compound of formula (I)according to the invention shows therapeutic efficacy especially againstdisorders dependent on protein tyrosine kinase (“protein tyrosine kinasedependent diseases”) such as FGFR, VEGFR2 (KDR), PDGF-R, cKIT, LCK,cABL, RET, especially proliferative diseases mediated FGFR kinaseactivity. The compounds of formula (I), that inhibit the proteintyrosine kinase activities mentioned, especially tyrosine proteinkinases mentioned above and below, can therefore be used in thetreatment of protein kinase dependent diseases. Thus, a compound offormula (I) is in particular useful in the treatment of diseasesidentified below.

FGFR dependent diseases include a wide variety of disorders orconditions known to the person skilled in the art.

A first group of FGFR dependents diseases relates to a benign ormalignant proliferative disease, e.g. a cancer, e.g. tumors and/ormetastasis (wherever located). In a preferred embodiment, theproliferative disease is a cancer. The proliferative diseases include,without being limited to, cancers of the bladder, cervix, or oralsquamous cell carcinomas (in particular with mutated FGFR3 and/orelevated FGFR3 expression), multiple myeloma (in particular with t(4,14)chromosomal translocation), breast cancers (in particular with geneamplification and/or protein overexpression of FGFR1, FGFR2 or FGFR4),endometrial cancer (in particular with FGFR2 mutations), hepatocellularcancer (in particular with elevated expression of FGFR3 or FGFR4 or FGFligands), any cancer type with an amplification of the 11q13 amplicon,which contains the FGF3, FGF4 and FGF19 loci, for example breast cancer,hepatocellular cancer, EMS myeloproliferative disorders (in particularwith abnormal FGFR1 fusion proteins), lymphomas (in particular withabnormal FGFR3 fusion proteins), glioblastomas (in particular with FGFR1abnormal expression or mutations), gastric carcinomas (in particularwith FGFR2 mutations or overexpression or FGFR3 mutations), pancreaticcarcinomas (in particular with abnormal FGFR1 or FGFR4 expression),prostate carcinomas (in particular with abnormal expression of FGFR1,FGFR4, or FGF ligands); pituitary tumors (in particular with abnormalFGFR4), any cancer that requires angiogenesis.

A second group of FGFR dependents diseases relates to non-cancerdisorders. Such non-cancer disorders include, without being limited to,benign skin tumors (in particular with FGFR3 activating mutations),skeletal disorders (in particular resulting from mutations in FGFRs)including achondroplasia, hypochondroplasia, severe achondroplasia withdevelopmental delay and acanthosis nigricans (SADDAN), thanatophoricdysplasia (TD), muenke coronal craniosynostosis, crouzon syndrome withacanthosis nigricans, both familial and sporadic forms of Pfeiffersyndrome; disorders related to alterations of phosphate homeostasis, forexample autosomal dominant hypophosphatemic rickets (ADHR, in particularrelated to FGF23 missense mutations), x-linked hypophosphatemic rickets(XLH; an x-linked dominant disorder related to inactivating mutations inthe PHEX gene), tumorinduced osteomalacia (TIO, an acquired disorder ofisolated phosphate), or fibrous dysplasia of the bone (FD).

A third group of FGFR dependent diseases relates to inflammatory orautoimmune diseases.

The inhibition of FGFR activity has been found to represent a means fortreating T cell mediated inflammatory or autoimmune diseases, as forexample in treatment of T-cell mediated inflammatory or autoimmunediseases including but not limited to rheumatoid arthritis (RA),collagen II arthritis, multiple sclerosis (MS), systemic lupuserythematosus (SLE), psoriasis, juvenile onset diabetes, Sjogren'sdisease, thyroid disease, sarcoidosis, autoimmune uveitis, inflammatorybowel disease (Crohn's and ulcerative colitis), celiac disease andmyasthenia gravis.

A fourth group of FGFR dependent diseases relates tot the groupconsisting of obesity, diabetes and/or diseases related thereto. Methodsof antagonizing FGFRs, especially FGFR1 or FGFR4, have also beendescribed to be useful in the treatment of obesity, diabetes and/ordiseases related thereto, such as metabolic syndrome, cardiovasculardiseases, hypertension, aberrant cholesterol and triglyceride levels,dermatological disorders e.g. infections, varicose veins, Acanthosisnigricans, eczema, exercise intolerance, diabetes type 2, insulinresistance, hypercholesterolemia, cholelithiasis, orthopedic injury,thromboembolic disease, coronary or vascular restriction (e.g.atherosclerosis), daytime sleepiness, sleep apnoea, end stage renaldisease, gallbladder disease, gout, heat disorders, impaired immuneresponse, impaired respiratory function, infections following wounds,infertility, liver disease, lower back pain, obstetric and gynecologicalcomplications, pancreatitis, stroke, surgical complications, urinarystress incontinence and/or gastrointestinal disorders.

Further, enhanced (especially bronchial) expression of FGFRs, especiallyFGFR1, has been reported to be associated with Chronic ObstructivePulmonary Disease (COPD).

Further, acidic Fibroblast Growth Factor (especially FGF-1) and FGFR1have also been described to be involved in aberrant signaling inretinoblastoma, leading to proliferation upon binding of FGF-1.

Non-FGFR protein kinase dependent diseases include VEGFR2 (KDR), PDGF,cKIT, LCK, cABL and RET dependent diseases and are especiallyproliferative diseases, preferably benign or especially malignanttumours (for example carcinoma of the kidneys, liver, adrenal glands,bladder, breast, stomach, ovaries, colon, rectum, prostate, pancreas,lungs, vagina or thyroid, sarcoma, glioblastomas and numerous tumours ofthe neck and head, as well as leukemias). They are able to bring aboutthe regression of tumours and to prevent the formation of tumourmetastases and the growth of (also micro)-metastases. In addition theycan be used in epidermal hyperproliferation (e.g. psoriasis), inprostate hyperplasia, and in the treatment of neoplasias, especially ofepithelial character, for example mammary carcinoma. It is also possibleto use the compounds of formula (I) in the treatment of diseases of theimmune system insofar as several or, especially, individual tyrosineprotein kinases are involved; furthermore, the compounds of formula (I)can be used also in the treatment of diseases of the central orperipheral nervous system where signal transmission by at least onetyrosine protein kinase, especially selected from those mentionedspecifically, is involved.

VEGFR2 (KDR) dependent diseases include a wide variety of disorders orconditions known to the person skilled in the art. Vascular endothelialgrowth factor receptor-2 (VEGFR2; KDR) is expressed on the primaryvascular endothelium and is essential for normal vascular development.Angiogenesis, or the sprouting of new blood vessels, is also a centralprocess in the growth of solid tumors. For many cancers, the extent ofvascularization of a tumor is a negative prognostic indicator signifyingaggressive disease and increased potential for metastasis. Recentefforts to understand the molecular basis of tumor-associatedangiogenesis have identified several potential therapeutic targets,including the receptor tyrosine kinases for the angiogenic factorvascular endothelial growth factor (VEGF). The compounds of formula (I)as inhibitors of VEGF-receptor tyrosine kinase activity, may primarilyinhibit the growth of blood vessels and are thus, for example, effectiveagainst a number of diseases associated with deregulated angiogenesis,especially diseases caused by ocular neovascularisation, especiallyretinopathies, such as diabetic retinopathy or age-related maculadegeneration, psoriasis, haemangioblastoma, such as haemangioma,mesangial cell proliferative disorders, such as chronic or acute renaldiseases, e.g. diabetic nephropathy, malignant nephrosclerosis,thrombotic microangiopathy syndromes or transplant rejection, orespecially inflammatory renal disease, such as glomerulonephritis,especially mesangioproliferative glomerulonephritis, haemolytic-uraemicsyndrome, diabetic nephropathy, hypertensive nephrosclerosis, atheroma,arterial restenosis, autoimmune diseases, diabetes, endometriosis,chronic asthma, and especially neoplastic diseases, for exampleso-called solid tumors (especially cancers of the gastrointestinaltract, the pancreas, breast, stomach, cervix, bladder, kidney, prostate,ovaries, endometrium, lung, brain, melanoma, Kaposi's sarcoma, squamouscell carcinoma of head and neck, malignant pleural mesotherioma,lymphoma or multiple myeloma) and liquid tumors (e.g. leukemias),especially those expressing KDR, are especially important. A compound offormula (I) inhibits the growth of tumours and is especially suited topreventing the metastatic spread of tumors and the growth ofmicrometastases. These diseases are thus also Protein kinase dependentdiseases.

PDGF dependent diseases include a wide variety of disorders orconditions known to the person skilled in the art. Compounds of theformula (I), in view of their activity as PDGF receptor inhibitors, arealso especially appropriate in the treatment of proliferate diseases,especially glioblastoma, small lung cancer, atherosclerosis, thrombosis,psoriasis, scleroderma or fibrosis.

cKIT dependent diseases include a wide variety of disorders orconditions known to the person skilled in the art. It is known that suchkinases are frequently aberrantly expressed in common human cancers suchas breast cancer, head and neck cancers, gastrointestinal cancer such ascolon, rectal or stomach cancer, leukemia, and ovarian, bronchial, lungor pancreatic cancer. KIT kinase expression has been documented in awide variety of human malignancies such as mastocytosis/mast cellleukemia, gastrointestinal stromal tumors (GIST), small cell lungcarcinoma (SCLC), sinonasal natural killer/T-cell lymphoma, testicularcancer (seminoma), thyroid carcinoma, malignant melanoma, ovariancarcinoma, adenoid cystic carcinoma, acute myelogenous leukemia (AML),breast carcinoma, pediatric T-cell acute lymphoblastic leukemia,angiosarcoma, anaplastic large cell lymphoma, endometrial carcinoma, andprostate carcinoma. The kinase activity of KIT has been implicated inthe pathophysiology of several of these—and additional tumors—includingbreast carcinoma, SCLC, GIST, germ cell tumors, mast cell leukemia,neuroblastoma, AML, melanoma and ovarian carcinoma. Further, C-kit is areceptor tyrosine kinase expressed on the surface of mast cells, towhich stem cell factor (SCF) is a ligand. Aberrant c-kit signaling is amediator of certain autoimmune diseases. Binding of SCF to the c-kitreceptor mediates various functions of the mast cell. As an importantmediator of mast cell function, c-kit plays a role in pathologiesassociated with mast cells (MC). C-kit functions through mast cellgeneration, which plays an important role in triggering autoimmunediseases.

LCK dependent diseases include a wide variety of disorders or conditionsknown to the person skilled in the art. LCK is a cytoplastic tyronsinekinase of the Src family expressed in T cells and natural killer cells.It is generally accepted that Lck activity is important for signalingmediated by the T cell receptor and leads to normal T cell developmentand activation. Thus, compounds of formula (I) are a usefulimmunosuppressive for the treatment of autoimmune and inflammatorydisorders and/or organ transplant rejection (in particular T cellmediated).

cABL dependent diseases include a wide variety of disorders orconditions known to the person skilled in the art. In CML, areciprocally balanced chromosomal translocation in hematopoietic stemcells (HSCs) produces the BCR-ABL hybrid gene. The latter encodes theoncogenic Bcr-Abl fusion protein. Whereas ABL encodes a tightlyregulated protein tyrosine kinase, which plays a fundamental role inregulating cell proliferation, adherence and apoptosis, the BCR-ABLfusion gene encodes as constitutively activated kinase, whichtrans-forms HSCs to produce a phenotype exhibiting deregulated clonalproliferation, reduced capacity to adhere to the bone marrow stroma anda reduces apoptotic response to mutagenic stimuli, which enable it toaccumulate progressively more malignant transformations. Compounds ofthe formula (I), in view of their activity as Abl protein tyrosunekinase inhibitors, are also especially appropriate in the treatment ofleukemias, e.g. CML or acute lymphoblastic leukemia (ALL).

RET dependent diseases include a wide variety of disorders or conditionsknown to the person skilled in the art. In humans, activating RETmutations are found in the inherited cancer sysndrome multiple endocrineneoplasia 2 and in sporadic medullary and papillary thyroid carcinomas.The specific type and location of RET mutations are strongly correlatedwith the disease phenotype and also have diagnostic and prognosticvalue. Further, RET—associated thyroid tumors encompass malignancies ofthe parafollicular C. cells and of follicular epithelial cells, of whichthe most common are papillary thyroid carcinomas. In addition, RETmutations cause the early onset cancer syndrome multiple endocrineneoloasia type 2 associated with several endocrine tumors including MTX,PC and parathyroid hyperplasia.

The invention also provides, in a third aspect, a combination of acompound of formula (I) and one or more further therapeutic agents. Acompound of formula (I) can be administered alone or in combination withone or more other therapeutic agents, possible combination therapytaking the form of fixed combinations or the administration of acompound of the invention and one or more other therapeutic agents beingstaggered or given independently of one another, or the combinedadministration of fixed combinations and one or more other therapeuticagents. A compound of formula (I) can besides or in addition beadministered especially for tumor therapy in combination withchemotherapy, radiotherapy, immunotherapy, surgical intervention, or acombination of these. Long-term therapy is equally possible as isadjuvant therapy in the context of other treatment strategies, asdescribed above. Other possible treatments are therapy to maintain thepatient's status after tumor regression, or even chemopreventivetherapy, for example in patients at risk.

Thus, a compound of the formula (I) may be used to advantage incombination with other antiproliferative compounds. Suchantiproliferative compounds include, but are not limited to aromataseinhibitors; antiestrogens; topoisomerase I inhibitors; topoisomerase IIinhibitors; microtubule active compounds; alkylating compounds; histonedeacetylase inhibitors; compounds which induce cell differentiationprocesses; cyclooxygenase inhibitors; MMP inhibittors; mTOR inhibitors;antineoplastic antimetabolites; platin compounds; compoundstargeting/decreasing a protein or lipid kinase activity and furtheranti-angiogenic compounds; compounds which target, decrease or inhibitthe activity of a protein or lipid phosphatase; gonadorelin agonists;anti-androgens; methionine aminopeptidase inhibitors; bisphosphonates;biological response modifiers; antiproliferative antibodies; heparanaseinhibitors; inhibitors of Ras oncogenic isoforms; telomerase inhibitors;proteasome inhibitors; compounds used in the treatment of hematologicmalignancies; compounds which target, decrease or inhibit the activityof Flt-3; Hsp90 inhibitors such as 17-AAG (17-allylaminogeldanamycin,NSC330507), 17-DMAG(17-dimethylaminoethylamino-17-demethoxy-geldanamycin, NSC707545),IPI-504, CNF1010, CNF2024, CNF1010 from Conforma Therapeutics;temozolomide (TEMODAL®); kinesin spindle protein inhibitors, such asSB715992 or SB743921 from GlaxoSmithKline, or pentamidine/chlorpromazinefrom CombinatoRx; MEK inhibitors such as ARRy142886 from ArrayPioPharma, AZD6244 from AstraZeneca, PD181461 from Pfizer, leucovorin,EDG binders, antileukemia compounds, ribonucleotide reductaseinhibittors, S-adenosylmethionine decarboxylase inhibitors,antiproliferative antibodies or other chemotherapeutic compounds.Further, alternatively or in addition they may be used in combinationwith other tumor treatment approaches, including surgery, ionizingradiation, photodynamic therapy, implants, e.g. with corticosteroids,hormones, or they may be used as radiosensitizers. Also, inanti-inflammatory and/or antiproliferative treatment, combination withanti-inflammatory drugs is included. Combination is also possible withantihistamine drug substances, bronchodilatatory drugs, NSAID orantagonists of chemokine receptors.

The term “aromatase inhibitor” as used herein relates to a compoundwhich inhibits the estrogen production, i.e. the conversion of thesubstrates androstenedione and testosterone to estrone and estradiol,respectively. The term includes, but is not limited to steroids,especially atamestane, exemestane and formestane and, in particular,non-steroids, especially aminoglutethimide, roglethimide,pyridoglutethimide, trilostane, testolactone, ketokonazole, vorozole,fadrozole, anastrozole and letrozole. Exemestane can be administered,e.g., in the form as it is marketed, e.g. under the trademark AROMASIN.Formestane can be administered, e.g., in the form as it is marketed,e.g. under the trademark LENTARON. Fadrozole can be administered, e.g.,in the form as it is marketed, e.g. under the trademark AFEMA.Anastrozole can be administered, e.g., in the form as it is marketed,e.g. under the trademark ARIMIDEX. Letrozole can be administered, e.g.,in the form as it is marketed, e.g. under the trademark FEMARA or FEMAR.Aminoglutethimide can be administered, e.g., in the form as it ismarketed, e.g. under the trademark ORIMETEN. A combination of theinvention comprising a chemotherapeutic agent which is an aromataseinhibitor is particularly useful for the treatment of hormone receptorpositive tumors, e.g. breast tumors.

The term “antiestrogen” as used herein relates to a compound whichantagonizes the effect of estrogens at the estrogen receptor level. Theterm includes, but is not limited to tamoxifen, fulvestrant, raloxifeneand raloxifene hydrochloride. Tamoxifen can be administered, e.g., inthe form as it is marketed, e.g. under the trademark NOLVADEX.Raloxifene hydrochloride can be administered, e.g., in the form as it ismarketed, e.g. under the trademark EVISTA. Fulvestrant can be formulatedas disclosed in U.S. Pat. No. 4,659,516 or it can be administered, e.g.,in the form as it is marketed, e.g. under the trademark FASLODEX. Acombination of the invention comprising a chemotherapeutic agent whichis an antiestrogen is particularly useful for the treatment of estrogenreceptor positive tumors, e.g. breast tumors.

The term “anti-androgen” as used herein relates to any substance whichis capable of inhibiting the biological effects of androgenic hormonesand includes, but is not limited to, bicalutamide (CASODEX), which canbe formulated, e.g. as disclosed in U.S. Pat. No. 4,636,505. The term“gonadorelin agonist” as used herein includes, but is not limited toabarelix, goserelin and goserelin acetate. Goserelin is disclosed inU.S. Pat. No. 4,100,274 and can be administered, e.g., in the form as itis marketed, e.g. under the trademark ZOLADEX. Abarelix can beformulated, e.g. as disclosed in U.S. Pat. No. 5,843,901.

The term “topoisomerase I inhibitor” as used herein includes, but is notlimited to topotecan, gimatecan, irinotecan, camptothecian and itsanalogues, 9-nitrocamptothecin and the macromolecular camptothecinconjugate PNU-166148 (compound A1 in WO99/17804). Irinotecan can beadministered, e.g. in the form as it is marketed, e.g. under thetrademark CAMPTOSAR. Topotecan can be administered, e.g., in the form asit is marketed, e.g. under the trademark HYCAMTIN.

The term “topoisomerase II inhibitor” as used herein includes, but isnot limited to the anthracyclines such as doxorubicin (includingliposomal formulation, e.g. CAELYX), daunorubicin, epirubicin,idarubicin and nemorubicin, the anthraquinones mitoxantrone andlosoxantrone, and the podophillotoxines etoposide and teniposide.Etoposide can be administered, e.g. in the form as it is marketed, e.g.under the trademark ETOPOPHOS. Teniposide can be administered, e.g. inthe form as it is marketed, e.g. under the trademark VM 26-BRISTOL.Doxorubicin can be administered, e.g. in the form as it is marketed,e.g. under the trademark ADRIBLASTIN or ADRIAMYCIN. Epirubicin can beadministered, e.g. in the form as it is marketed, e.g. under thetrademark FARMORUBICIN. Idarubicin can be administered, e.g. in the formas it is marketed, e.g. under the trademark ZAVEDOS. Mitoxantrone can beadministered, e.g. in the form as it is marketed, e.g. under thetrademark NOVANTRON.

The term “microtubule active compound” relates to microtubulestabilizing, microtubule destabilizing compounds and microtublinpolymerization inhibitors including, but not limited to taxanes, e.g.paclitaxel and docetaxel, vinca alkaloids, e.g., vinblastine, especiallyvinblastine sulfate, vincristine especially vincristine sulfate, andvinorelbine, discodermolides, cochicine and epothilones and derivativesthereof, e.g. epothilone B or D or derivatives thereof. Paclitaxel maybe administered e.g. in the form as it is marketed, e.g. TAXOL.Docetaxel can be administered, e.g., in the form as it is marketed, e.g.under the trademark TAXOTERE. Vinblastine sulfate can be administered,e.g., in the form as it is marketed, e.g. under the trademark VINBLASTINR.P. Vincristine sulfate can be administered, e.g., in the form as it ismarketed, e.g. under the trademark FARMISTIN. Discodermolide can beobtained, e.g., as disclosed in U.S. Pat. No. 5,010,099. Also includedare Epothilone derivatives which are disclosed in WO98/10121, U.S. Pat.No. 6,194,181, WO98/25929, WO98/08849, WO99/43653, WO98/22461 andWO00/31247. Especially preferred are Epothilone A and/or B.

The term “alkylating compound” as used herein includes, but is notlimited to, cyclophosphamide, ifosfamide, melphalan or nitrosourea (BCNUor Gliadel). Cyclophosphamide can be administered, e.g., in the form asit is marketed, e.g. under the trademark CYCLOSTIN. Ifosfamide can beadministered, e.g., in the form as it is marketed, e.g. under thetrademark HOLOXAN.

The term “histone deacetylase inhibitors” or “HDAC inhibitors” relatesto compounds which inhibit the histone deacetylase and which possessantiproliferative activity. This includes compounds disclosed inWO02/22577, especiallyN-hydroxy-3-[4-[[(2-hydroxyethyl)[2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide,N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamideand pharmaceutically acceptable salts thereof. It further especiallyincludes Suberoylanilide hydroxamic acid (SAHA).

The term “antineoplastic antimetabolite” includes, but is not limitedto, 5-Fluorouracil or 5-FU, capecitabine, gemcitabine, DNA demethylatingcompounds, such as 5-azacytidine and decitabine, methotrexate andedatrexate, and folic acid antagonists such as pemetrexed. Capecitabinecan be administered, e.g., in the form as it is marketed, e.g. under thetrademark XELODA. Gemcitabine can be administered, e.g., in the form asit is marketed, e.g. under the trademark GEMZAR.

The term “platin compound” as used herein includes, but is not limitedto, carboplatin, cisplatin, cisplatinum and oxaliplatin. Carboplatin canbe administered, e.g., in the form as it is marketed, e.g. under thetrademark CARBOPLAT. Oxaliplatin can be administered, e.g., in the formas it is marketed, e.g. under the trademark ELOXATIN.

The term “compounds targeting/decreasing a protein or lipid kinaseactivity”; or a “protein or lipid phosphatase activity”; or “furtheranti-angiogenic compounds” as used herein includes, but is not limitedto, protein tyrosine kinase and/or serine and/or threonine kinaseinhibitors or lipid kinase inhibitors, e.g.,

a) compounds targeting, decreasing or inhibiting the activity of theplatelet-derived growth factor-receptors (PDGFR), such as compoundswhich target, decrease or inhibit the activity of PDGFR, especiallycompounds which inhibit the PDGF receptor, e.g. aN-phenyl-2-pyrimidine-amine derivative, e.g. imatinib, SU101, SU6668 andGFB-111;b) compounds targeting, decreasing or inhibiting the activity of thefibroblast growth factorreceptors (FGFR);c) compounds targeting, decreasing or inhibiting the activity of theinsulin-like growth factor receptor I (IGF-1R), such as compounds whichtarget, decrease or inhibit the activity of IGF-1R, especially compoundswhich inhibit the kinase activity of IGF-1 receptor, such as thosecompounds disclosed in WO02/092599, or antibodies that target theextracellular domain of IGF-1 receptor or its growth factors;d) compounds targeting, decreasing or inhibiting the activity of the Trkreceptor tyrosine kinase family, or ephrin B4 inhibitors;e) compounds targeting, decreasing or inhibiting the activity of the Axlreceptor tyrosine kinase family;f) compounds targeting, decreasing or inhibiting the activity of the Retreceptor tyrosine kinase;g) compounds targeting, decreasing or inhibiting the activity of theKit/SCFR receptor tyrosine kinase, e.g. imatinib;h) compounds targeting, decreasing or inhibiting the activity of theC-kit receptor tyrosine kinases—(part of the PDGFR family), such ascompounds which target, decrease or inhibit the activity of the c-Kitreceptor tyrosine kinase family, especially compounds which inhibit thec-Kit receptor, e.g. imatinib;i) compounds targeting, decreasing or inhibiting the activity of membersof the c-Abl family, their gene-fusion products (e.g. BCR-Abl kinase)and mutants, such as compounds which target decrease or inhibit theactivity of c-Abl family members and their gene fusion products, e.g. aN-phenyl-2-pyrimidine-amine derivative, e.g. imatinib or nilotinib(AMN107); PD180970; AG957; NSC 680410; PD173955 from ParkeDavis; ordasatinib (BMS-354825)j) compounds targeting, decreasing or inhibiting the activity of membersof the protein kinase C (PKC) and Raf family of serine/threoninekinases, members of the MEK, SRC, JAK, FAK, PDK1, PKB/Akt, and Ras/MAPKfamily members, and/or members of the cyclin-dependent kinase family(CDK) and are especially those staurosporine derivatives disclosed inU.S. Pat. No. 5,093,330, e.g. midostaurin; examples of further compoundsinclude e.g. UCN-01, safingol, BAY 43-9006, Bryostatin 1, Perifosine;Ilmofosine; RO 318220 and RO 320432; GO 6976; Isis 3521;LY333531/LY379196; isochinoline compounds such as those disclosed inWO00/09495; FTIs; PD184352 or QAN697 (a PI3K inhibitor) or AT7519 (CDKinhibitor);k) compounds targeting, decreasing or inhibiting the activity ofprotein-tyrosine kinase inhibitors, such as compounds which target,decrease or inhibit the activity of protein-tyrosine kinase inhibitorsinclude imatinib mesylate (GLEEVEC) or tyrphostin. A tyrphostin ispreferably a low molecular weight (Mr<1500) compound, or apharmaceutically acceptable salt thereof, especially a compound selectedfrom the benzylidenemalonitrile class or the S-arylbenzenemalonirile orbisubstrate quinoline class of compounds, more especially any compoundselected from the group consisting of Tyrphostin A23/RG-50810; AG 99;Tyrphostin AG 213; Tyrphostin AG 1748; Tyrphostin AG 490; TyrphostinB44; Tyrphostin B44 (+) enantiomer; Tyrphostin AG 555; AG 494;Tyrphostin AG 556, AG957 and adaphostin(4-{[(2,5-dihydroxyphenyl)methyl]amino}-benzoic acid adamantyl ester;NSC 680410, adaphostin);l) compounds targeting, decreasing or inhibiting the activity of theepidermal growth factor family of receptor tyrosine kinases (EGFR,ErbB2, ErbB3, ErbB4 as homo- or heterodimers) and their mutants, such ascompounds which target, decrease or inhibit the activity of theepidermal growth factor receptor family are especially compounds,proteins or antibodies which inhibit members of the EGF receptortyrosine kinase family, e.g. EGF receptor, ErbB2, ErbB3 and ErbB4 orbind to EGF or EGF related ligands, and are in particular thosecompounds, proteins or monoclonal antibodies generically andspecifically disclosed in WO97/02266, e.g. the compound of ex. 39, or inEP 0 564 409, WO99/03854, EP 0520722, EP 0 566 226, EP 0 787 722, EP 0837 063, U.S. Pat. No. 5,747,498, WO98/10767, WO97/30034, WO97/49688,WO97/38983 and, especially, WO96/30347 (e.g. compound known as CP358774), WO96/33980 (e.g. compound ZD 1839) and WO95/03283 (e.g.compound ZM105180); e.g. trastuzumab (Herceptin™), cetuximab (Erbitux™),Iressa, Tarceva, OSI-774, CI-1033, EKB-569, GW-2016, E1.1, E2.4, E2.5,E6.2, E6.4, E2.11, E6.3 or E7.6.3, and 7H-pyrrolo-[2,3-d]pyrimidinederivatives which are disclosed in WO03/013541; andm) compounds targeting, decreasing or inhibiting the activity of thec-Met receptor, such as compounds which target, decrease or inhibit theactivity of c-Met, especially compounds which inhibit the kinaseactivity of c-Met receptor, or antibodies that target the extracellulardomain of c-Met or bind to HGF.

Further anti-angiogenic compounds include compounds having anothermechanism for their activity, e.g. unrelated to protein or lipid kinaseinhibition e.g. thalidomide (THALOMID) and TNP-470.

The term “Compounds which target, decrease or inhibit the activity of aprotein or lipid phosphatase” includes, but is not limited to inhibitorsof phosphatase 1, phosphatase 2A, or CDC25, e.g. okadaic acid or aderivative thereof.

The term “Compounds which induce cell differentiation processes”includes, but is not limited to e.g. retinoic acid, α- γ- orδ-tocopherol or α- γ- or δ-tocotrienol.

The term “cyclooxygenase inhibitor” as used herein includes, but is notlimited to, e.g. Cox-2 inhibitors, 5-alkyl substituted2-arylaminophenylacetic acid and derivatives, such as celecoxib(CELEBREX), rofecoxib (VIOXX), etoricoxib, valdecoxib or a5-alkyl-2-arylaminophenylacetic acid, e.g.5-methyl-2-(2′-chloro-6′-fluoroanilino)phenyl acetic acid, lumiracoxib.

The term “bisphosphonates” as used herein includes, but is not limitedto, etridonic, clodronic, tiludronic, pamidronic, alendronic,ibandronic, risedronic and zoledronic acid. “Etridonic acid” can beadministered, e.g., in the form as it is marketed, e.g. under thetrademark DIDRONEL. “Clodronic acid” can be administered, e.g., in theform as it is marketed, e.g. under the trademark BONEFOS. “Tiludronicacid” can be administered, e.g., in the form as it is marketed, e.g.under the trademark SKELID. “Pamidronic acid” can be administered, e.g.in the form as it is marketed, e.g. under the trademark AREDIA™.“Alendronic acid” can be administered, e.g., in the form as it ismarketed, e.g. under the trademark FOSAMAX. “Ibandronic acid” can beadministered, e.g., in the form as it is marketed, e.g. under thetrademark BONDRANAT. “Risedronic acid” can be administered, e.g., in theform as it is marketed, e.g. under the trademark ACTONEL. “Zoledronicacid” can be administered, e.g. in the form as it is marketed, e.g.under the trademark ZOMETA. The term “mTOR inhibitors” relates tocompounds which inhibit the mammalian target of rapamycin (mTOR) andwhich possess antiproliferative activity such as sirolimus (Rapamune®),everolimus (Certican™), CCI-779 and ABT578.

The term “heparanase inhibitor” as used herein refers to compounds whichtarget, decrease or inhibit heparin sulfate degradation. The termincludes, but is not limited to, PI-88. The term “biological responsemodifier” as used herein refers to a lymphokine or interferons, e.g.interferon γ.

The term “inhibitor of Ras oncogenic isoforms”, e.g. H-Ras, K-Ras, orN-Ras, as used herein refers to compounds which target, decrease orinhibit the oncogenic activity of Ras e.g. a “farnesyl transferaseinhibitor” e.g. L-744832, DK8G557 or R115777 (Zarnestra). The term“telomerase inhibitor” as used herein refers to compounds which target,decrease or inhibit the activity of telomerase. Compounds which target,decrease or inhibit the activity of telomerase are especially compoundswhich inhibit the telomerase receptor, e.g. telomestatin.

The term “methionine aminopeptidase inhibitor” as used herein refers tocompounds which target, decrease or inhibit the activity of methionineaminopeptidase. Compounds which target, decrease or inhibit the activityof methionine aminopeptidase are e.g. bengamide or a derivative thereof.

The term “proteasome inhibitor” as used herein refers to compounds whichtarget, decrease or inhibit the activity of the proteasome. Compoundswhich target, decrease or inhibit the activity of the proteasome includee.g. Bortezomid (Velcade™) and MLN 341.

The term “matrix metalloproteinase inhibitor” or (“MMP” inhibitor) asused herein includes, but is not limited to, collagen peptidomimetic andnonpeptidomimetic inhibitors, tetracycline derivatives, e.g. hydroxamatepeptidomimetic inhibitor batimastat and its orally bioavailable analoguemarimastat (BB-2516), prinomastat (AG3340), metastat (NSC 683551)BMS-279251, BAY 12-9566, TAA211, MMI270B or AAJ996.

The term “compounds used in the treatment of hematologic malignancies”as used herein includes, but is not limited to, FMS-like tyrosine kinaseinhibitors e.g. compounds targeting, decreasing or inhibiting theactivity of FMS-like tyrosine kinase receptors (Flt-3R); interferon,1-b-D-arabinofuransylcytosine (ara-c) and bisulfan; and ALK inhibitorse.g. compounds which target, decrease or inhibit anaplastic lymphomakinase.

Compounds which target, decrease or inhibit the activity of FMS-liketyrosine kinase receptors (Flt-3R) are especially compounds, proteins orantibodies which inhibit members of the Flt-3R receptor kinase family,e.g. PKC412, midostaurin, a staurosporine derivative, SU11248 andMLN518.

The term “HSP90 inhibitors” as used herein includes, but is not limitedto, compounds targeting, decreasing or inhibiting the intrinsic ATPaseactivity of HSP90; degrading, targeting, decreasing or inhibiting theHSP90 client proteins via the ubiquitin proteosome pathway. Compoundstargeting, decreasing or inhibiting the intrinsic ATPase activity ofHSP90 are especially compounds, proteins or antibodies which inhibit theATPase activity of HSP90 e.g., 17-allylamino, 17-demethoxygeldanamycin(17AAG), a geldanamycin derivative; other geldanamycin relatedcompounds; radicicol and HDAC inhibitors.

The term “antiproliferative antibodies” as used herein includes, but isnot limited to, trastuzumab (Herceptin™), Trastuzumab-DM1, erbitux,bevacizumab (Avastin™), rituximab (Rituxan®), PRO64553 (anti-CD40) and2C4 Antibody. By antibodies is meant e.g. intact monoclonal antibodies,polyclonal antibodies, multispecific antibodies formed from at least 2intact antibodies, and antibodies fragments so long as they exhibit thedesired biological activity.

For the treatment of acute myeloid leukemia (AML), compounds of formula(I) can be used in combination with standard leukemia therapies,especially in combination with therapies used for the treatment of AML.In particular, compounds of formula (I) can be administered incombination with, e.g., farnesyl transferase inhibitors and/or otherdrugs useful for the treatment of AML, such as Daunorubicin, Adriamycin,Ara-C, VP-16, Teniposide, Mitoxantrone, Idarubicin, Carboplatinum andPKC412.

The term “antileukemic compounds” includes, for example, Ara-C, apyrimidine analog, which is the 2″-alpha-hydroxy ribose (arabinoside)derivative of deoxycytidine. Also included is the purine analog ofhypoxanthine, 6-mercaptopurine (6-MP) and fludarabine phosphate.Compounds which target, decrease or inhibit activity of histonedeacetylase (HDAC) inhibitors such as sodium butyrate andsuberoylanilide hydroxamic acid (SAHA) inhibit the activity of theenzymes known as histone deacetylases. Specific HDAC inhibitors includeMS275, SAHA, FK228 (formerly FR901228), Trichostatin A and compoundsdisclosed in U.S. Pat. No. 6,552,065, in particular,N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide,or a pharmaceutically acceptable salt thereof andN-hydroxy-3-[4-[(2-hydroxyethyl){2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide,or a pharmaceutically acceptable salt thereof, especially the lactatesalt.

“Somatostatin receptor antagonists” as used herein refers to compoundswhich target, treat or inhibit the somatostatin receptor such asoctreotide, and SOM230.

“Tumor cell damaging approaches” refer to approaches such as ionizingradiation. The term “ionizing radiation” referred to above andhereinafter means ionizing radiation that occurs as eitherelectromagnetic rays (such as X-rays and gamma rays) or particles (suchas alpha and beta particles). Ionizing radiation is provided in, but notlimited to, radiation therapy and is known in the art. See Hellman,Principles of Radiation Therapy, Cancer, in Principles and Practice ofOncology, Devita et al., Eds., 4^(th) Edition, Vol. 1, pp. 248-275(1993).

The term “EDG binders” as used herein refers a class ofimmunosuppressants that modulates lymphocyte recirculation, such asFTY720.

The term “ribonucleotide reductase inhibitors” includes, but is notlimited to pyrimidine or purine nucleoside analogs including, but notlimited to, fludarabine and/or cytosine arabinoside (ara-C),6-thioguanine, 5-fluorouracil, cladribine, 6-mercaptopurine (especiallyin combination with ara-C against ALL) and/or pentostatin.Ribonucleotide reductase inhibitors are especially hydroxyurea or2-hydroxy-1H-isoindole-1,3-dione derivatives, such as PL-1, PL-2, PL-3,PL-4, PL-5, PL-6, PL-7 or PL-8 mentioned in Nandy et al., ActaOncologica, Vol. 33, No. 8, pp. 953-961 (1994).

The term “S-adenosylmethionine decarboxylase inhibitors” as used hereinincludes, but is not limited to the compounds disclosed in U.S. Pat. No.5,461,076.

Also included are in particular those compounds, proteins or monoclonalantibodies of VEGF disclosed in WO98/35958, e.g.1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or a pharmaceuticallyacceptable salt thereof, e.g. the succinate, or in WO00/09495,WO00/27820, WO00/59509, WO98/11223, WO00/27819 and EP 0 769 947; thoseas described by Prewett et al, Cancer Res, Vol. 59, pp. 5209-5218(1999); Yuan et al., Proc Natl Acad Sci USA, Vol. 93, pp. 14765-14770(1996); Zhu et al., Cancer Res, Vol. 58, pp. 3209-3214 (1998); andMordenti et al., Toxicol Pathol, Vol. 27, No. 1, pp. 14-21 (1999); inWO00/37502 and WO94/10202; ANGIOSTATIN, described by O'Reilly et al.,Cell, Vol. 79, pp. 315-328 (1994); ENDOSTATIN, described by O'Reilly etal., Cell, Vol. 88, pp. 277-285 (1997); anthranilic acid amides; ZD4190;ZD6474; SU5416; SU6668; bevacizumab; or anti-VEGF antibodies oranti-VEGF receptor antibodies, e.g. rhuMAb and RHUFab, VEGF aptamer e.g.Macugon; FLT-4 inhibitors, FLT-3 inhibitors, VEGFR-2 IgG1 antibody,Angiozyme (RPI 4610) and Bevacizumab (Avastin™).

“Photodynamic therapy” as used herein refers to therapy which usescertain chemicals known as photosensitizing compounds to treat orprevent cancers. Examples of photodynamic therapy include treatment withcompounds, such as e.g. VISUDYNE and porfimer sodium.

“Angiostatic steroids” as used herein refers to compounds which block orinhibit angiogenesis, such as, e.g., anecortave, triamcinolone,hydrocortisone, 11-α-epihydrocotisol, cortexolone,17α-hydroxyprogesterone, corticosterone, desoxycorticosterone,testosterone, estrone and dexamethasone.

“Implants containing corticosteroids” as used herein includes, but isnot limited to compounds, such as e.g. fluocinolone, dexamethasone.

“Other chemotherapeutic compounds” include, but are not limited to,plant alkaloids, hormonal compounds and antagonists; biological responsemodifiers, preferably lymphokines or interferons; antisenseoligonucleotides or oligonucleotide derivatives; shRNA or siRNA; ormiscellaneous compounds or compounds with other or unknown mechanism ofaction.

The compounds of the invention are also useful as co-therapeuticcompounds for use in combination with other drug substances such asanti-inflammatory, bronchodilatory or antihistamine drug substances,particularly in the treatment of inflammatory diseases such as thosementioned hereinbefore, for example as potentiators of therapeuticactivity of such drugs or as a means of reducing required dosaging orpotential side effects of such drugs. A compound of the invention may bemixed with the other drug substance in a fixed pharmaceuticalcomposition or it may be administered separately, before, simultaneouslywith or after the other drug substance. Accordingly the inventionincludes a combination of a compound of the invention as hereinbeforedescribed with an anti-inflammator or antihistamine drug substance, saidcompound of the invention and said drug substance being in the same ordifferent pharmaceutical composition.

Suitable anti-inflammatory drugs include steroids, in particularglucocorticosteroids such as budesonide, beclamethasone dipropionate,fluticasone propionate, ciclesonide or mometasone furoate, or steroidsdescribed in WO02/88167, WO02/12266, WO02/100879, WO02/00679 (especiallythose of Examples 3, 11, 14, 17, 19, 26, 34, 37, 39, 51, 60, 67, 72, 73,90, 99 and 101), WO03/035668, WO03/048181, WO03/062259, WO03/064445,WO03/072592, non-steroidal glucocorticoid receptor agonists such asthose described in WO00/00531, WO02/10143, WO03/082280, WO03/082787,WO03/104195, WO04/005229; LTB4 antagonists such LY293111, CGS025019C,CP-195543, SC-53228, BIIL 284, ONO 4057, SB 209247 and those describedin U.S. Pat. No. 5,451,700; LTD4 antagonists such as montelukast andzafirlukast; PDE4 inhibitors such cilomilast (Ariflo® GlaxoSmithKline),Roflumilast (Byk Gulden), V-11294A (Napp), BAY19-8004 (Bayer),SCH-351591 (Schering-Plough), Arofylline (Almirall Prodesfarma),PD189659/PD168787 (Parke-Davis), AWD-12-281 (Asta Medica), CDC-801(Celgene), SeICID™ CC-10004 (Celgene), VM554/UM565 (Vernalis), T-440(Tanabe), KW-4490 (Kyowa Hakko Kogyo), and those disclosed inWO92/19594, WO93/19749, WO93/19750, WO93/19751, WO98/18796, WO99/16766,WO01/13953, WO03/104204, WO03/104205, WO03/39544, WO04/000814,WO04/000839, WO04/005258, WO04/018450, WO04/018451, WO04/018457,WO04/018465, WO04/018431, WO04/018449, WO04/018450, WO04/018451,WO04/018457, WO04/018465, WO04/019944, WO04/019945, WO04/045607 andWO04/037805; A2a agonists such as those disclosed in EP 409595A2, EP1052264, EP 1241176, WO94/17090, WO96/02543, WO96/02553, WO98/28319,WO99/24449, WO99/24450, WO99/24451, WO99/38877, WO99/41267, WO99/67263,WO99/67264, WO99/67265, WO99/67266, WO00/23457, WO00/77018, WO00/78774,WO01/23399, WO01/27130, WO01/27131, WO01/60835, WO01/94368, WO02/00676,WO02/22630, WO02/96462, WO03/086408, WO04/039762, WO04/039766,WO04/045618 and WO04/046083; A2b antagonists such as those described inWO02/42298; and beta-2 adrenoceptor agonists such as albuterol(salbutamol), metaproterenol, terbutaline, salmeterol fenoterol,procaterol, and especially, formoterol and pharmaceutically acceptablesalts thereof, and compounds (in free or salt or solvate form) offormula (I) of WO0075114, preferably compounds of the Examples thereof,especially a compound of formula

and pharmaceutically acceptable salts thereof, as well as compounds (infree or salt or solvate form) of formula (I) of WO04/16601, and alsocompounds of WO04/033412. Suitable bronchodilatory drugs includeanticholinergic or antimuscarinic compounds, in particular ipratropiumbromide, oxitropium bromide, tiotropium salts and CHF 4226 (Chiesi), andglycopyrrolate, but also those described in WO01/04118, WO02/51841,WO02/53564, WO03/00840, WO03/87094, WO04/05285, WO02/00652, WO03/53966,EP 424021, U.S. Pat. No. 5,171,744, U.S. Pat. No. 3,714,357, WO03/33495and WO04/018422.

Suitable antihistamine drug substances include cetirizine hydrochloride,acetaminophen, clemastine fumarate, promethazine, loratidine,desloratidine, diphenhydramine and fexofenadine hydrochloride,activastine, astemizole, azelastine, ebastine, epinastine, mizolastineand tefenadine as well as those disclosed in WO03/099807, WO04/026841and JP 2004107299.

Other useful combinations of compounds of the invention withanti-inflammatory drugs are those with antagonists of chemokinereceptors, e.g. CCR-1, CCR-2, CCR-3, CCR-4, CCR-5, CCR-6, CCR-7, CCR-8,CCR-9 and CCR10, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, particularly CCR-5antagonists such as Schering-Plough antagonists SC-351125, SCH-55700 andSCH-D, Takeda antagonists such asN-[[4-[[[6,7-dihydro-2-(4-methylphenyl)-5H-benzo-cyclohepten-8-yl]carbonyl]amino]phenyl]-methyl]tetrahydro-N,N-dimethyl-2H-pyran-4-aminiumchloride (TAK-770), and CCR-5 antagonists described in U.S. Pat. No.6,166,037 (particularly claims 18 and 19), WO00/66558 (particularlyclaim 8), WO00/66559 (particularly claims 9), WO04/018425 andWO04/026873.

Therapeutic agents for possible combination are especially one or moreantiproliferative, cytostatic or cytotoxic compounds, for example one orseveral agents selected from the group which includes, but is notlimited to, an inhibitor of polyamine biosynthesis, an inhibitor of aprotein kinase, especially of a serine/threonine protein kinase, such asprotein kinase C, or of a tyrosine protein kinase, such as the EGFreceptor tyrosine kinase, e.g. Iressa®, the VEGF receptor tyrosinekinase, e.g. PTK787 or Avastin®, or the PDGF receptor tyrosine kinase,e.g. STI571 (Glivec®), a cytokine, a negative growth regulator, such asTGF-β or IFN-β, an aromatase inhibitor, e.g. letrozole (Femara®) oranastrozole, an inhibitor of the interaction of an SH2 domain with aphosphorylated protein, antiestrogens, topoisomerase I inhibitors, suchas irinotecan, topoisomerase II inhibitors, microtubule active agents,e.g. paclitaxel or an epothilone, alkylating agents, antiproliferativeantimetabolites, such as gemcitabine or capecitabine, platin compounds,such as carboplatin or cis-platin, bisphosphonates, e.g. AREDIA® orZOMETA®, and monoclonal antibodies, e.g. against HER2, such astrastuzumab.

The structure of the active agents identified by code nos., generic ortrade names may be taken from the actual edition of the standardcompendium “The Merck Index” or from databases, e.g. PatentsInternational (e.g. IMS World Publications).

The above-mentioned compounds, which can be used in combination with acompound of the formula (I), can be prepared and administered asdescribed in the art, such as in the documents cited above.

Thus, the invention relates in a further aspect to a combinationcomprising a therapeutically effective amount of a compound of formula(I) in free form or in pharmaceutically acceptable salt form and asecond drug substance, for simultaneous or sequential administration.

The invention also provides, in a further aspect, a pharmaceuticalpreparation (composition), comprising a compound of formula (I) asdefined herein, or a pharmaceutically acceptable salt of such acompound, or a hydrate or solvate thereof, and at least onepharmaceutically acceptable carrier and/or diluents and optionally oneor more further drug substances.

The compounds of the invention may be administered by any conventionalroute, in particular parenterally, for example in the form of injectablesolutions or suspensions, enterally, e.g. orally, for example in theform of tablets or capsules, topically, e.g. in the form of lotions,gels, ointments or creams, or in a nasal or a suppository form. Topicaladministration is e.g. to the skin. A further form of topicaladministration is to the eye. Pharmaceutical compositions comprising acompound of the invention in association with at least onepharmaceutical acceptable carrier or diluent may be manufactured inconventional manner by mixing with a pharmaceutically acceptable carrieror diluent.

The invention relates also to pharmaceutical compositions comprising aneffective amount, especially an amount effective in the treatment of oneof the above-mentioned diseases (=disorders), of a compound of formula(I) or a pharmaceutically acceptable salt thereof together with one ormore pharmaceutically acceptable carriers that are suitable for topical,enteral, for example oral or rectal, or parenteral administration andthat may be inorganic or organic, solid or liquid. There can be used fororal administration especially tablets or gelatin capsules that comprisethe active ingredient together with diluents, for example lactose,dextrose, mannitol, and/or glycerol, and/or lubricants and/orpolyethylene glycol. Tablets may also comprise binders, for examplemagnesium aluminum silicate, starches, such as corn, wheat or ricestarch, gelatin, methylcellulose, sodium carboxymethylcellulose and/orpolyvinylpyrrolidone, and, if desired, disintegrators, for examplestarches, agar, alginic acid or a salt thereof, such as sodium alginate,and/or effervescent mixtures, or adsorbents, dyes, flavorings andsweeteners. It is also possible to use the pharmacologically activecompounds of the present invention in the form of parenterallyadministrable compositions or in the form of infusion solutions. Thepharmaceutical compositions may be sterilized and/or may compriseexcipients, for example preservatives, stabilisers, wetting compoundsand/or emulsifiers, solubilisers, salts for regulating the osmoticpressure and/or buffers. The present pharmaceutical compositions, whichmay, if desired, comprise other pharmacologically active substances areprepared in a manner known per se, for example by means of conventionalmixing, granulating, confectioning, dissolving or lyophilisingprocesses, and comprise approximately from 1% to 99%, especially fromapprox. 1% to approx. 20%, active ingredient(s).

The dosage of the active ingredient to be applied to a warm-bloodedanimal depends upon a variety of factors including type, species, age,weight, sex and medical condition of the patient; the severity of thecondition to be treated; the route of administration; the renal andhepatic function of the patient; and the particular compound employed. Aphysician, clinician or veterinarian of ordinary skill can readilydetermine and prescribe the effective amount of the drug required toprevent, counter or arrest the progress of the condition. Optimalprecision in achieving concentration of drug within the range thatyields efficacy without toxicity requires a regimen based on thekinetics of the drug's availability to target sites. This involves aconsideration of the distribution, equilibrium, and elimination of adrug. The dose of a compound of the formula (I) or a pharmaceuticallyacceptable salt thereof to be administered to warmblooded animals, forexample humans of approximately 70 kg body weight, is preferably fromapproximately 3 mg to approximately 5 g, more preferably fromapproximately 10 mg to approximately 1.5 g per person per day, dividedpreferably into 1 to 3 single doses which may, for example, be of thesame size. Usually, children receive half of the adult dose.

In a further aspect, the invention relates to a compound of formula (I)or a pharmaceutically acceptable salt, as a medicament/for use as amedicament, in particular for the treatment of one or more Proteintyrosine kinase mediated diseases.

In a further aspect, the invention relates to the use of a compound offormula (I) or a pharmaceutically acceptable salt, as active ingredientin a medicament, in particular for the treatment of one or more Proteintyrosine kinase mediated diseases.

In a further aspect, the invention relates to the use of a compound offormula (I) or a pharmaceutically acceptable salt, as medicament, inparticular for the treatment of one or more Protein tyrosine kinasemediated diseases.

In a further aspect, the invention relates to the use of a compound offormula (I) or a pharmaceutically acceptable salt, for the manufactureof a medicament for the treatment of one or more Protein tyrosine kinasemediated diseases.

In a further aspect, the invention relates to a compound of formula (I)or a pharmaceutically acceptable salt of such a compound, for use in amethod for the treatment of a subject in need thereof, especially forthe treatment of a Protein tyrosine kinase mediated disease, mostespecially in a patient requiring such treatment.

In a further aspect, the invention relates to a method for the treatmentof a disease which responds to an inhibition of a FGFR (such as FGFR3)kinase, which comprises administering a compound of formula (I) or apharmaceutically acceptable salt thereof, wherein the radicals andsymbols have the meanings as defined above, especially in a quantityeffective against said disease, to a warm-blooded animal requiring suchtreatment.

In a further aspect, the invention relates to a pharmaceuticalcomposition comprising a compound of formula (I) as active ingredient inassociation with at least one pharmaceutical carrier or diluent. Suchcompositions may be manufactured in conventional manner. In a furtheraspect, the invention relates to a method of treatment of one or moreProtein tyrosine kinase mediated diseases, in a subject in need of suchtreatment, which comprises administering to such subject atherapeutically effective amount of compound of formula I.

In a further aspect, the invention relates to pharmaceuticalcompositions comprising: (a) an effective amount of compound of formula(I) and pharmaceutically acceptable salts, pharmaceutically acceptableprodrugs, and pharmaceutically active metabolites thereof; and (b) oneor more pharmaceutically acceptable excipients and/or diluents.

In a further aspect, the invention relates to a pharmaceuticalcomposition for treatment of a disease, e.g. of solid or liquid tumoursin warm-blooded animals, including humans, comprising a dose effectivein the treatment of said disease of a compound of the formula (I) asdescribed above or a pharmaceutically acceptable salt of such a compoundtogether with a pharmaceutically acceptable carrier (=carrier material).

The invention also provides, in a further aspect, methods ofmanufacturing a compound of formula (I) and intermediates and theirmethods of manufacturing; such intermediates are useful for themanufacturing of a compound of formula (I). A compound of the formula(I) may be prepared by processes that, though not applied hitherto forthe new compounds of the present invention where they thus form newprocesses, are known per se, the following scheme illustrates methodsfor such preparation.

Preferably, a process for the manufacture of a compound of the formula(I) comprises either

Method A) reacting a carboxylic acid of the formula (II),

wherein the substituents are as defined for a compound of the formula(I) with an amine of the formula (III)

optionally in the presence of a diluent (such as a polar organicsolvent), optionally in the presence of a reaction aid (such as DMAP orTBTU), optionally in the presence of a base (such as an amine) to obtaina compound of formula I; or

Method B) reacting a compound of formula (X)

wherein the substituents are as defined for a compound of the formula(I) and Hal represents halo (in particular bromo) with a boron compoundof the formula (V)

wherein the substituents are as defined for a compound of the formula(I) and L₂B represents represents a boronic acid residue or an esterthereof (such as (HO)₂B—) or4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl-), optionally in thepresence of a diluent (such as an apolar organic solvent), optionally inthe presence of a catalyst (such as a homogeneous Pd-catalyst),optionally in the presence of an reaction aid (such as an inorganicbase) to obtain a compound of formula I;and, if desired, converting a compound of the formula (I) obtainedaccording to method A) or method B) into a different compound of theformula (I), and/or converting an obtainable salt of a compound of theformula (I) into a different salt thereof, and/or converting anobtainable free compound of the formula (I) into a salt thereof, and/orseparating an obtainable isomer of a compound of the formula (I) fromone or more different obtainable isomers of the formula I.

Method A) is particularly useful for manufacturing of compounds whereinX represents N (such as formula (I-A), (I-B), (I-C); while method B) isparticular useful for manufacturing of compounds wherein X represents CH(such as formula (I-D)).

Reaction Conditions

Where temperatures are given hereinbefore or hereinafter, “about” has tobe added, as minor deviations from the numeric values given, e.g.variations of ±10%, are tolerable. All reactions may take place in thepresence of one or more diluents and/or solvents. Protective gases, suchas argon, may be used. The starting materials may be used in equimolaramounts; alternatively, a compound may be used in excess, e.g. tofunction as a solvent or to shift equilibrium or to generally acceleratereaction rates. Reaction aids, such as acids, bases or catalysts may beadded in suitable amounts, as known in the field, required by a reactionand in line with generally known procedures.

Intermediates and final products can be worked up and/or purifiedaccording to standard methods, e.g. using chromatographic methods,distribution methods, (re-) crystallization, and the like. Intermediatesmay be directly used in the further reaction step or may be subject toone or more work up and/or purification steps. Additionally,intermediates may be subject to furtherderivatization/functionalization, as the case may be. For example,substitution of an aryl/heteroaryl ring may take place to introduceadditional substituents (such as chloro, fluoro).

Starting materials may be used as commercially available, and/or subjectto one or more work up and/or purification steps and/or produced insitu.

Amide Forming Reaction

Such reactions are generally known in the field. The reaction typicallytakes place in the presence of an activating agent (such as TBTU orothers) which may be added in a slight excess and in the presence of atert. amine and in the presence of one or more diluents (such as polaraprotic diluents). Typically, the reaction takes place at r.t., reactiontimes may vary, good conversion rates are typically obtained after 18hours. Further details may be found in the examples.

Suzuki-Coupling

This reaction is, inter alia, useful for manufacturing of compounds offormula (I) according to method B) as described above. Reactionconditions, starting materials and catalysts for a Suzuki(-Miyaura)reaction are generally known in the field. This reaction typically takesplace by palladium-catalyzed crosscoupling of organoboranes (e.g. offormula (V) or a reactive derivative thereof, with a halogen derivative(e.g. of the formula (IV) or (X)). The reaction may be typicallyperformed in analogy to the procedure described by K. Jones, M. Keenan,and F. Hibbert [Synlett, 1996, (6), 509-510].

Protecting Groups

Protected derivatives of the compounds of the invention can be made bymeans known to those of ordinary skill in the art. Protecting groups aresuch groups that are typically no longer present in the final compoundsonce they are removed, while groups that remain as substituents are notprotecting groups in the sense used here which are groups that are addedat a starting material or intermediate stage and removed to obtain afinal compound. Also in the case of conversions of a compound of theformula (I) into a different compound of the formula (I), protectinggroups may be introduced and removed, if useful or required.

The protecting groups may already be present in precursors and shouldprotect the functional groups concerned against unwanted secondaryreactions, such as acylations, etherifications, esterifications,oxidations, solvolysis, and similar reactions. It is a characteristic ofprotecting groups that they lend themselves readily, i.e. withoutundesired secondary reactions, to removal, typically by acetolysis,protonolysis, solvolysis, reduction, photolysis or also by enzymeactivity, for example under conditions analogous to physiologicalconditions, and that they are not present in the end-products. Thespecialist knows, or can easily establish, which protecting groups aresuitable with the reactions mentioned above and below.

The protection of such functional groups by such protecting groups, theprotecting groups themselves, and their removal reactions are describedfor example in standard reference works, such as J. F. W. McOmie,“Protective Groups in Organic Chemistry”, Plenum Press, London and NewYork 1973, in T. W. Greene, “Protective Groups in Organic Synthesis”,Third edition, Wiley, New York 1999, in “The Peptides”; Volume 3(editors: E. Gross and J. Meienhofer), Academic Press, London and NewYork 1981, in “Methoden der organischen Chemie” (Methods of organicchemistry), Houben Weyl, 4th edition, Volume 15/I, Georg Thieme Verlag,Stuttgart 1974, in H.-D. Jakubke and H. Jescheit, “Aminosäuren, Peptide,Proteine” (Amino acids, peptides, proteins), Verlag Chemie, Weinheim,Deerfield Beach, and Basel 1982, and in Jochen Lehmann, “Chemie derKohlenhydrate: Monosaccharide and Derivate” (Chemistry of carbohydrates:monosaccharides and derivatives), Georg Thieme Verlag, Stuttgart 1974.

Optional Reactions and Conversions

A compound of the formula (I) may be converted into a different compoundof the formula (I). The following description provides a non-limitingoverview of particular relevant optional reactions and conversions:

Benzyl groups: For example, in a compound of the formula (I) having abenzyl which is optionally substituted (e.g. methoxybenzyl), said benzylmoiety may be removed by hydrogenation, e.g. in the presence of a noblemetal catalyst, such as palladium on coal, in an appropriate solvent,such as an alcohol, e.g. methanol, at appropriate temperatures, e.g.from 0 to 50° C., in the case of removal from the piperazine nitrogen inthe additional presence of an acid, e.g. HCl, to yield the correspondingcompound wherein instead of the benzyl moiety a hydrogen is present.

N-oxides: A compound of formula (I) can be converted to a correspondingN-oxide. The reaction is typically carried out with a suitable oxidizingagent, preferably a peroxide, for example m-chloroperbenzoic acid, in asuitable solvent, e.g. halogenated hydrocarbon, typically chloroform ordichloromethane, or in a lower alkanecarboxylic acid, typically aceticacid, preferably at a temperature between 0° C. and the boilingtemperature of the reaction mixture, especially at about roomtemperature. Compounds of formula (I) in unoxidized form can typicallybe prepared from N-oxides of compounds of formula (I) by treating with areducing agent (e.g., sulfur, sulfur dioxide, triphenyl phosphine,lithium borohydride, sodium borohydride, phosphorus trichloride,tribromide, or the like) in a suitable inert organic solvent (e.g.acetonitrile, ethanol, aqueous dioxane, or the like) at 0 to 80° C.

Salts of compounds of formula (I) having at least one salt-forming groupmay be prepared in a manner known per se. For example, an acid additionsalt of compounds of formula (I) with basic groups (e.g. basic nitrogen)can be typically obtained in customary manner, e.g. by treating acompound of the formula (I) with an acid or a suitable anion exchangereagent. A salt of a compound of formula (I) having acid groups may betypically formed by treating the compound with a metal compound, such asan alkali metal salt of a suitable organic carboxylic acid, e.g. thesodium salt of 2-ethylhexanoic acid, with an organic alkali metal oralkaline earth metal compound, such as the corresponding hydroxide,carbonate or hydrogen carbonate, such as sodium or potassium hydroxide,carbonate or hydrogen carbonate, with a corresponding calcium compoundor with ammonia or a suitable organic amine, stoichiometric amounts oronly a small excess of the salt-forming agent preferably being used.Internal salts of compounds of formula (I) containing acid and basicsalt-forming groups, e.g. a free carboxy group and a free amino group,may be formed, e.g. by the neutralization of salts, such as acidaddition salts, to the isoelectric point, e.g. with weak bases, or bytreatment with ion exchangers. A salt of a compound of the formula (I)can be typically converted in customary manner into the free compound; ametal or ammonium salt can be converted, for example, by treatment witha suitable acid, and an acid addition salt, for example, by treatmentwith a suitable basic agent into a different salt. In both cases,suitable ion exchangers may be used.

Prodrug derivatives of the compounds of the invention can be prepared bymethods known to those of ordinary skill in the art (e.g., for furtherdetails see Saulnier et al., (1994), Bioorganic and Medicinal ChemistryLetters, Vol. 4, p. 1985). For example, appropriate prodrugs can betypically prepared by reacting a non-derivatized compound of theinvention with a suitable carbamylating agent (e.g.,1,1-acyloxyalkylcarbanochloridate, para-nitrophenyl carbonate, or thelike).

Solvates:

Compounds of the present invention can be conveniently prepared, orformed during the process of the invention, as solvates (e.g.,hydrates). Hydrates of compounds of the present invention can beconveniently prepared by recrystallization from an aqueous/organicsolvent mixture, using organic solvents such as dioxin, tetrahydrofuranor methanol.

For example, in a compound of the formula (I) wherein a substituentcarries an amino or amino-C₁-C₇-alkyl substituent, the amino can beconverted into acylamino, e.g. C₁-C₇-alkanoylamino orC₁-C₇-alkanesulfonylamino, typically by reaction with a correspondingC₁-C₇-alkanoylhalogenide or C₁-C₇-alkanesulfonylhalogenide, e.g. acorresponding chloride, in the presence of a tertiary nitrogen base,such as triethylamine or pyridine, in the absence or presence of anappropriate solvent, such a methylene chloride, for example attemperatures in the range from −20 to 50° C., e.g. at about roomtemperature.

In a compound of the formula (I) wherein a substituent carries a cyanosubstituent, the cyano may be converted to an aminomethyl group, e.g. byhydrogenation in the presence of an appropriate metal catalyst, such asRaney Nickel or Raney Cobalt, in an appropriate solvent, e.g. a loweralkanol, such as methanol and/or ethanol, for example at temperatures inthe range from −20 to 50° C., e.g. at about room temperature.

In a compound of the formula (I) wherein a substituent carries acarboxyl group (—COOH), the latter can be converted into an amide group,e.g. an N—C₁-C₇-alkyl-carbamoyl group, typically by reaction with thecorresponding amine, e.g. in the presence of a coupling agent, thatforms a preferred reactive derivative of the carboxyl group in situ, forexample dicyclohexylcarbodiimide/1-hydroxybenzotriazole (DCC/HOBT);bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOPCI);O-(1,2-dihydro-2-oxo-1-pyridyl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (TPTU);O-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(TBTU);(benzotriazol-1-yloxy)-tripyrrolidinophosphonium-hexafluorophosphate(PyBOP), O-(1H-6-chlorobenzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride/hydroxybenzotriazole or/1-hydroxy-7-azabenzotriazole(EDC/HOBT or EDC/HOAt) or HOAt alone, or with(1-chloro-2-methyl-propenyl)-dimethylamine. For review of some otherpossible coupling agents, see e.g. Klauser; Bodansky, Synthesis (1972),453-463. The reaction mixture is preferably stirred at a temperature ofbetween approximately −20 and 50° C., especially between 0° C. and 30°C., e.g. at room temperature.

Salts of a compound of formula (I) with a salt-forming group may beprepared in a manner known per se. Acid addition salts of compounds offormula (I) may thus be obtained by treatment with an acid or with asuitable anion exchange reagent. A salt with two acid molecules (forexample a dihalogenide of a compound of formula I) may also be convertedinto a salt with one acid molecule per compound (for example amonohalogenide); this may be typically done by heating to a melt, or forexample by heating as a solid under a high vacuum at elevatedtemperature, for example from 130 to 170° C., one molecule of the acidbeing expelled per molecule of a compound of formula I. Salts canusually be converted to free compounds, e.g. by treating with suitablebasic compounds, for example with alkali metal carbonates, alkali metalhydrogencarbonates, or alkali metal hydroxides, typically K₂CO₃ orsodium NaOH.

Stereoisomeric mixtures, e.g. mixtures of diastereomers, can beseparated into their corresponding isomers in a manner known per se bymeans of suitable separation methods. Diastereomeric mixtures forexample may be separated into their individual diastereomers by means offractionated crystallization, chromatography, solvent distribution, andsimilar procedures. This separation may take place either at the levelof a starting compound or in a compound of formula (I) itself.Enantiomers may be separated through the formation of diastereomericsalts, for example by salt formation with an enantiomer-pure chiralacid, or by means of chromatography, for example by HPLC, usingchromatographic substrates with chiral ligands. A more detaileddescription of the techniques applicable to the resolution ofstereoisomers of compounds from their racemic mixture can be found in J.Jacques, A. Collet, S. H. Wilen, “Enantiomers, Racemates andResolutions”, Wiley, 1981.

It should be emphasized that reactions analogous to the conversionsmentioned in this chapter may also take place at the level ofappropriate intermediates (and are thus useful in the preparation ofcorresponding starting materials).

Insofar as the production of the starting materials is not particularlydescribed, the compounds are known or can be prepared analogously tomethods known in the art or as disclosed in the Examples hereinafter.

One of skill in the art will appreciate that the above transformationsare only representative of methods for preparation of the compounds ofthe present invention, and that other well known methods can similarlybe used.

Starting Materials:

The starting materials of the formulae II, III, IV and V, as well asother starting materials mentioned herein, e.g. below, can be preparedaccording to or in analogy to methods that are known in the art, areknown in the art and/or are commercially available. Novel startingmaterials, as well as processes for the preparation thereof, arelikewise an embodiment of the present invention. In the preferredembodiments, such starting materials are used and the reaction chosenare selected so as to enable the preferred compounds to be obtained.Wherein the starting materials and intermediates R¹, R², R^(A1), R^(A2),R^(B1), R^(B1), X, ring A, ring B, m and n are used (“the substituentsof formula (I)”), these symbols preferably have the meanings given for acompound of the formula (I), if not indicated otherwise.

In the starting materials (including intermediates), which may also beused and/or obtained as salts where appropriate and expedient, thesubstituents are preferably as defined for a compound of the formula I.

Compounds of the formula (II) are known or may be prepared by processesthat, though not applied hitherto for the compounds of the formula (II)where they thus form new processes, are known per se, the followingscheme illustrates methods for such preparation. A process for themanufacture of a compound of the formula (II) comprises

method A), step 1: reacting first a compound of formula (IV)

wherein the substituents are as defined for a compound of the formula(I) and Hal represents halo (in particular bromo) with a boron compoundof the formula (V)

wherein the substituents are as defined for a compound of the formula(I) and L₂B represents represents a boronic acid residue or an esterthereof (such as (HO)₂B—) or4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl-), optionally in thepresence of a diluent (such as an apolar organic solvent), optionally inthe presence of a catalyst (such as a homogeneous Pd-catalyst),optionally in the presence of an reaction aid (such as an inorganicbase); step 2: converting the thus obtained compound, optionally afterpurification or isolation, with CuCN, optionally in the presence of apolar organic solvent (such as NMP) into the corresponding cyanoderivative;

step 3: hydrolysing the thus obtained compound, optionally afterpurification or isolation, optionally in the presence of an polarorganic solvent, to obtain a compound of formula (II);

or, method B), hydrolizing an ester of formula (IIX)

wherein the substituents are as defined for a compound of the formula(I) and R′ represents lower alkyl (in particular ethyl) under basicconditions, optionally in the prsende of a diluent, to obtain a compoundof formula (II);and, if desired, converting a compound of the formula (II) obtained intoa different compound of the formula (II), and/or converting anobtainable salt of a compound of the formula (II) into a different saltthereof, and/or converting an obtainable free compound of the formula(II) into a salt thereof, and/or separating an obtainable isomer of acompound of the formula (II) from one or more different obtainableisomers of the formula (II).

The subsequent conversion of a compound of formula (II) into anothercompound of formula (II) is further illustrated by the following scheme.

In this scheme, the substituents have the meaning as defined herein.Thus, compounds of formula (II), in particular wherein ring B representsphenyl, a halogenation step may take place once a compound of formula(II) is formed. Such subsequent reaction step (halogenation step) isparticular suitable if a substituent —R^(B2)—R^(B1) (such as fluoro orchloro) is to be introduced in one or both of the ortho-position(s) ofring B. Thus, the invention relates also to a process of manufacturing acompound of formula (II) wherein a Suzuki-coupling reaction as describedabove is followed by a substitution reaction, in particular ahalogenation reaction of ring B.

Compounds of the formula (III) are known or may be prepared by processesthat, though not applied hitherto for the compounds of the formula (III)where they thus form new processes, are known per se, the followingscheme illustrates methods for such preparation. A process for themanufacture of a compound of the formula (III) comprises the step ofreducing a compound of formula (IX)

wherein the substituents are as defined for a compound of the formula(I) with a reducing agent, optionally in the presence of a diluentand, if desired, converting a compound of the formula (III) obtainedinto a different compound of the formula (III), and/or converting anobtainable salt of a compound of the formula (III) into a different saltthereof, and/or converting an obtainable free compound of the formula(III) into a salt thereof, and/or separating an obtainable isomer of acompound of the formula (III) from one or more different obtainableisomers of the formula (III).

Compounds of the formula (IV) are known or may be prepared by processesthat, though not applied hitherto for the compounds of the formula (IV)where they thus form new processes, are known per se, the followingscheme illustrates methods for such preparation.

A process for the manufacture of a compound of the formula (IV) whereinX represents N, comprises the step of reacting a compound of formula(VI)

wherein R¹′ represents either R¹ or R² as defined for a compound of theformula (I) and with a compound of formula (VII),

wherein Hal represents halo, in particular bromo, optionally in thepresence of a diluentand, if desired, converting a compound of the formula (IV) obtained intoa different compound of the formula (IV), and/or converting anobtainable salt of a compound of the formula (IV) into a different saltthereof, and/or converting an obtainable free compound of the formula(IV) into a salt thereof, and/or separating an obtainable isomer of acompound of the formula (IV) from one or more different obtainableisomers of the formula (IV).

Compounds of the formula (V) are known or may be prepared by processesthat, though not applied hitherto for the compounds of the formula (V)where they thus form new processes, are known per se, the followingscheme illustrates methods for such preparation. A process for themanufacture of a compound of the formula (V) comprises the step ofreacting a compound of formula (XIII)

wherein the substituents are as defined for a compound of the formula(I) and hal represents halogen, in particular bromo, first with alithiation agent (such as butyllitium), optionally in the presence of adiluent, followed by reaction with a boronic acid or derivative thereof(such as trimethylboranate or bis-pinacolate-diboron)and, if desired, converting a compound of the formula (V) obtained intoa different compound of the formula (V), and/or converting an obtainablesalt of a compound of the formula (V) into a different salt thereof,and/or converting an obtainable free compound of the formula (V) into asalt thereof, and/or separating an obtainable isomer of a compound ofthe formula (V) from one or more different obtainable isomers of theformula (V).

Compounds of the formula (X) are known or may be prepared by processesthat, though not applied hitherto for the compounds of the formula (X)where they thus form new processes, are known per se, the followingscheme illustrates methods for such preparation.

A process for the manufacture of a compound of the formula (X) comprisesthe step of reacting a compound of formula (XI)

wherein the substituents are as defined for a compound of the formula(I) (in particular wherein X represents CH) and hal represents halo (inparticular bromo) with an amine of formula (III)

wherein the substituents are as defined for a compound of the formula(I), optionally in the presence of a diluent (such as a polor organicsolvent), optionally in the presence of a reaction aid (such as DMAP orTBTU), optionally in the presence of a base (such as an amine) to obtaina compound of formula (X)and, if desired, converting a compound of the formula (X) obtained intoa different compound of the formula (X), and/or converting an obtainablesalt of a compound of the formula (X) into a different salt thereof,and/or converting an obtainable free compound of the formula (X) into asalt thereof, and/or separating an obtainable isomer of a compound ofthe formula (X) from one or more different obtainable isomers of theformula (X).

This process is particular useful for compounds of formula (X), whereinX represents CH.

Compounds of the formula (XI) are known or may be prepared by processesthat, though not applied hitherto for the compounds of the formula (XI)where they thus form new processes, are known per se, the followingscheme illustrates methods for such preparation. A process for themanufacture of a compound of the formula (XI) comprises the step ofoxidizing a compound of formula (XII)

wherein the substituents are as defined for a compound of the formula(I) (in particular wherein X represents CH) and hal represents halo (inparticular bromo) with an oxidizing agent (such as KMnO₄) optionally ina diluentand, if desired, converting a compound of the formula (XI) obtained intoa different compound of the formula (XI), and/or converting anobtainable salt of a compound of the formula (XI) into a different saltthereof, and/or converting an obtainable free compound of the formula(XI) into a salt thereof, and/or separating an obtainable isomer of acompound of the formula (XI) from one or more different obtainableisomers of the formula (XI).

This process is particular useful for compounds of formula (X), whereinX represents CH.

The following examples illustrate the invention without limiting thescope thereof.

Temperatures are measured in degrees Celsius. Unless otherwiseindicated, the reactions take place at rt. Microwave Apparatus: EmrysOptimizer (Biotage)

Analytical HPLC conditions are as follows:

System 1: Linear gradient 20-100% solvent A in 5 min+1.5 min 100%solvent A; detection at 215 nm, flow rate 1 mL/min at 30° C. Column:Nucleosil 100-3 C18 (70×4.0 mm). Solvent A=CH₃CN+0.1% TFA; SolventB=H₂O+0.1% TFA.

System 2: 40% Solvent A for 5 min and then linear gradient 40-100%solvent A in 5 min+5 min 100% solvent A, flow rate 0.8 mL/min. Column:C18 XDB (250×4.6 mm). Solvent A=CH₃CN; Solvent B=20 mM NH₄OAc in H₂O.

System 3: Linear gradient 30-100% solvent A in 4 min+2 min 100% solventA; flow rate 0.8 mL/min. Column: Hypersil C18 (250×4.6 mm). SolventA=CH₃CN; Solvent B=H₂O+0.1% TFA.

The following Abbreviations and Acronyms are used:

AcOH acetic acid Boc₂O tert-butoxycarbonyl anhydride bp boiling pointbrine saturated solution of NaCl in water CH₃CN acetonitrile Cs₂CO₃cesium carbonate CuCN copper (I) cyanide DCM dichloromethane conc.concentrated DIEA diisopropylethylamine DMAP 4-(dimethylamino) pyridineDME 1,2-dimethoxyethane DMF dimethyl formamide DMP1,3-dimethyl-3,4,5,6-tetrahydro-2-(1H)-pyrimidinone DMSOdimethylsulfoxide equiv equivalent(s) Et₂O diethyl ether EtOAc ethylacetate EtOH ethanol h hour(s) Hex hexane HCl hydrochloric acid H₂Owater HPLC high pressure liquid chromatography KOH potassium hydroxyde Lliter(s) LiAlH₄ lithium aluminum hydride LiOH lithium hydroxyde mCPBAm-cloroperbenzoic acid Me methyl MeOH methanol mL milliliter(s) minminute(s) m.p. melting point MPLC medium pressure liquid chromatographyMS mass spectrum NaBH₄ sodium borohydride Na₂CO₃ sodium carbonate NaHsodium hydride NaHCO₃ sodium bicarbonate NaOH sodium hydroxyde Na₂SO₄sodium sulfate NBS N-bromosuccinimide NH₄OAc ammonium acetate NMP1-methyl-2-pyrrolidone NMR Nuclear Magnetic Resonance PdCl₂(dppf)[1,1′-bis(diphenylphosphino) ferrocene]dichloro- palladium(II) Pd(PPh₃)₄tetrakis(triphenylphosphine) palladium(0) Pd(PhCN)₂Cl₂Bis(benzonitrile)palladium(II)chloride Ph phenyl PPTS p-toluensulfonicacid R_(f) ratio of fronts (TLC) rt room temperature SelectFluor1-chloromethyl-4-fluoro-1,4-diazobicyclo[2.2.2]octanebis(tetrafluoroborate) TBTUO-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate TFACF₃COOH THF tetrahydrofuran TLC thin layer chromatography t_(R) time ofretention wt. weight

For convenience, the following synthetic schemes are provided, wherein

scheme 1 relates to examples 1-81

scheme 2 relates to examples 82-84

scheme 3 relates to examples 85-87

scheme 4 relates to examples 88-96

scheme 5 relates to examples 174-178

schemes 6 and 7 relate to examples 179-187

Example 1 8-(2,6-Dichloro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylicacid [4-(4-ethyl-piperazin-1-yl)-phenyl]-amide

A mixture of propylphosphonic anhydride (50% in DMF, 0.31 mL, 0.53 mmol,2 equiv), 8-(2,6-dichloro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylicacid (100 mg, 0.26 mmol) (Step 1.1), 4-(4-ethylpiperazin-1-yl)-aniline(Step 1.9) (65 mg, 0.32 mmol, 1.2 equiv), DMAP (2 mg), and Et₃N (0.37mL, 2.65 mmol, 10 equiv) in DMF (2.0 mL), was stirred for 18 h at rt,under an argon atmosphere. The reaction mixture was diluted with EtOAcand H₂O. The aqueous layer was separated and extracted with EtOAc. Thecombined organic phase was washed with brine, dried (Na₂SO₄), filteredand concentrated. The residue was purified by trituration in Et₂O toafford the title compound as a yellow solid: ES-MS: 565.9 [M+H]⁺;t_(R)=4.26 min (System 1).

Step 1.1: 8-(2,6-Dichloro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylicacid

Sulfuryl chloride (1.7 mL, 21.3 mmol, 2 equiv) was added dropwise to acold (5° C.) suspension of8-(3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid (Step 1.2) (3.3g, 10.6 mmol) in CH₃CN (30 mL). The reaction mixture was stirred at 5°C. for 2 h, quenched by addition of H₂O, and concentrated. Triturationof the residue in H₂O provided 4.0 g of the title compound as a whitesolid: ESI-MS: 378.9 [M+H]⁺; t_(R)=4.54 min (System 1).

Step 1.2: 8-(3,5-Dimethoxy-phenyl)-quinoxaline-5-carboxylic acid

KOH (6.0 g, 107 mmol, 10 equiv) was added to8-(3,5-dimethoxy-phenyl)-quinoxaline-5-carbonitrile (Step 1.3) (3.12 g,10.7 mmol) in ethylene glycol (30 mL). The reaction mixture was stirredat 150° C. for 3 h (a solution was obtained), allowed to cool to rt,diluted with Et₂O/H₂O, and extracted with Et₂O. The aqueous phase wasacidified to pH 5 by addition of HCl. Vacuum filtration of the resultingsuspension afforded 3.3 g of the title compound as a yellow solid:ESI-MS: 311.0 [M+H]⁺; t_(R)=4.34 min (System 1).

Step 1.3: 8-(3,5-Dimethoxy-phenyl)-quinoxaline-5-carbonitrile

A mixture of 5-bromo-8-(3,5-dimethoxy-phenyl)-quinoxaline (Step 1.4)(4.54 g, 13.2 mmol) and CuCN (1.54 g, 17.1 mmol, 1.3 equiv) in NMP (50mL) was stirred for 2 h at 180° C., under an argon atmosphere. Thereaction mixture was allowed to cool to rt, diluted with EtOAc (10%aqueous solution of ethylenediamine) (150 mL), and filtered to afford1.19 g (batch 1) of the title compound as a yellow solid. The filtratewas extracted with DCM. The organic phase was washed with H₂O and brine,dried (Na₂SO₄), filtered and concentrated. The residue was triturated inEtOAc to provide 2.31 g (batch 2) of the title compound: ESI-MS: 292.1[M+H]⁺; t_(R)=4.53 min (System 1).

Step 1.4: 5-Bromo-8-(3,5-dimethoxy-phenyl)-quinoxaline

A mixture of 3,5-dimethoxyphenylboronic acid (Step 1.8) (3.38 g, 18.6mmol) in EtOH (15 mL) was added dropwise to a mixture of5,8-dibromo-quinoxaline (Step 1.5) (10.7 g, 37.1 mmol, 2 equiv),PdCl₂(dppf) (530 mg, 0.7 mmol, 0.03 equiv), Na₂CO₃ (2 M solution in H₂O,37 mL, 74.3 mmol, 4 equiv) in toluene (100 mL) at 105° C., under anargon atmosphere. The reaction mixture was stirred at 105° C. for 2 h,allowed to cool to rt, diluted with EtOAc and H₂O, filtered through apad of celite and extracted with EtOAc. The organic phase was washedwith H₂O and brine, dried (Na₂SO₄), filtered and concentrated in vacuo.The crude product was purified by trituration in DCM, followed by silicagel column chromatography (Hex/EtOAc, 4:1) to afford 4.54 g of the titlecompound as a yellow solid: ES-MS: 345.0 [M+H]⁺; t_(R)=5.13 min (System1); R_(f)=0.17 (Hex/EtOAc, 4:1).

Step 1.5: 5,8-Dibromo-quinoxaline

A 40% aqueous solution of glyoxal (8.8 M, 6.3 mL, 55.1 mmol, 1.3 equiv)was added to a suspension of 3,6-dibromo-benzene-1,2-diamine (Step 1.6)(11.3 g, 42.4 mmol) in EtOH (280 mL). The reaction mixture was heated toreflux for 3 h and allowed to cool to rt overnight. Vacuum filtration ofthe reaction mixture afforded 9.7 g of the title compound as a yellowsolid: APCI-MS: 286.2/288.1/290.1 [M−1]⁻; t_(R)=4.40 min (System 1).

Step 1.6: 3,6-Dibromo-benzene-1,2-diamine

NaBH₄ (26 g, 680 mmol, 10 equiv) was added portionwise (2 h) to avigorously stirred suspension of 4,7-dibromo-benzo[1,2,5]thiadiazole(Step 1.7) (20 g, 68.0 mmol) in EtOH (400 mL), under a nitrogenatmosphere and keeping the internal temperature below 15° C. Thereaction mixture was allowed to warm to 30° C., stirred for 1 h, cooledto 5° C., quenched by addition of H₂O (50 mL), and concentrated. Theresidue was diluted with Et₂O/H₂O. The resulting suspension was filteredand the filtrate extracted with Et₂O. The organic phase was washed withH₂O and brine, dried (Na₂SO₄), filtered and concentrated. The residuewas triturated in hexane to provide 12 g of the title compound as awhite solid: ESI-MS: 262.9/264.9/266.9 [M−H]⁻; t_(R)=4.20 min (System1).

Step 1.7: 4,7-Dibromo-benzo[1,2,5]thiadiazole

Bromine (18.6 mL, 265 mmol, 1.2 equiv) was added to a refluxing solutionof 1,2,5-benzothiazole (30 g, 220 mmol) in HBr (48% in H₂O, 150 mL). Thereaction mixture was stirred for 4 h at reflux and allowed to cool tort. The resulting solid was collected by vacuum filtration, washed withH₂O, dried under vacuum, and triturated in MeOH to afford 63 g of thetitle compound as an off-white solid: ¹H NMR (400 MHz, DMSO-d6) δ(ppm):8.00 (s, 2H); t_(R)=5.05 min (System 1).

Step 1.8: 3,5-dimethoxyphenylboronic acid

t-BuLi (1.7 M in pentatne, 63 mL, 106 mmol, 2.1 equiv) was addeddropwise to a cold (−78° C.) solution of 3,5-dimethoxy-bromobenzene (11g, 50.7 mmol) in THF (400 mL), under an argon atmosphere. The yellowmixture si stirred for 45 min at −78° C. Trimethyl borate (20 mL, 179mmol, 3.5 equiv) was then added. The colorless reaction mixture wasallowed to warm to 0° C., quenched by addition of a saturated solutionof NH₄Cl (5 mL), and concentrated. The residue was diluted withEtOAc/NH₄Cl (saturated aqueous solution), and extracted with EtOAc. Theorganic phase was dried (Na₂SO₄), filtered and concentrated. The residuewas triturated in Et₂O to provide 6.8 g of the title compound as a whitesolid: ESI-MS: 183.1 [M+H]⁺; t_(R)=2.70 min (System 1).

Step 1.9: 4-(4-Ethylpiperazin-1-yl)-aniline

A suspension of 1-ethyl-4-(4-nitro-phenyl)-piperazine (Step 1.10) (6.2g, 26.35 mmol) and Raney nickel (2 g) in MeOH (120 mL) was stirred for 7h at rt, under a hydrogen atmosphere. The reaction mixture was filteredthrough a pad of celite and concentrated to afford 5.3 g of the titlecompound as a violet solid: ESI-MS: 206.1 [M+H]⁺; TLC: R_(f)=0.15(DCM/MeOH+1% NH₃ ^(aq), 9:1).

Step 1.10:1-Ethyl-4-(4-nitro-phenyl)-piperazine

A mixture of 1-bromo-4-nitrobenzene (6 g, 29.7 mmol) and1-ethylpiperazine (7.6 mL, 59.4 mmol, 2 equiv) was heated to 80° C. for15 h. After cooling to rt, the reaction mixture was diluted with H₂O andDCM/MeOH (9:1, v/v). The aqueous layer was separated and extracted withDCM/MeOH, 9:1. The organic phase was washed with brine, dried (sodiumsulfate), filtered and concentrated. Purification of the residue bysilica gel column chromatography (DCM/MeOH+1% NH₃ ^(aq), 9:1) afforded6.2 g of the title compound as a yellow solid: ESI-MS: 236.0 [M+H]⁺;t_(R)=2.35 min (purity: 100%, system 1); TLC: R_(f)=0.50 (DCM/MeOH+1%NH₃ ^(aq), 9:1).

Example 2 8-(2,6-Dichloro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylicacid [3-(4-ethyl-piperazin-1-yl)-phenyl]-amide

The title compound was prepared in analogy to the procedure described inExample 1 but using 3-(4-ethylpiperazin-1-yl)-aniline (Step 2.1).Purification of the crude product by silica gel column chromatography(DCM/MeOH/NH₃ ^(aq), 96.5:2.5:1) afforded 147 mg of the title compoundas a yellow solid: ESI-MS: 565.9/567.9 [M+H]⁺; t_(R)=4.35 min (System1); TLC: R_(f)=0.30 (DCM/MeOH/NH₃ ^(aq), 96.5:2.5:1).

Step 2.1: 3-(4-Ethylpiperazin-1-yl)-aniline

The title compound was prepared in analogy to the procedure described inStep 1.9 but using 1-ethyl-4-(3-nitro-phenyl)-piperazine (Step 2.2).Title compound: ESI-MS: 206.2 [M+H]⁺; t_(R)=2.49 min (System 1).

Step 2.2: 1-Ethyl-4-(3-nitro-phenyl)-piperazine

A mixture of 2-fluoro-4-nitrobenzene (3.2 mL, 29.7 mmol) and1-ethylpiperazine (7.6 mL, 59.4 mmol, 2 equiv) was heated to reflux for117 h. After cooling to rt, the reaction mixture was diluted with H₂Oand DCM/MeOH, 9:1. The aqueous layer was separated and extracted withDCM/MeOH, 9:1. The organic phase was washed with brine, dried (Na₂SO₄),filtered and concentrated. Purification of the residue by silica gelcolumn chromatography (DCM/MeOH, 1:0→95:5) afforded 6 g of the titlecompound as a brown oil: ESI-MS: 236.0 [M+H]⁺; t_(R)=2.49 min (System1); TLC: R_(f)=0.26 (DCM/MeOH, 95:5).

Example 3 8-(2,6-Dichloro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylicacid (4-carbamoyl-phenyl)-amide

The title compound was prepared in analogy to the procedure described inExample 1 but using 4-aminobenzamide. Purification of the crude productby silica gel column chromatography (DCM/MeOH, 95:5), followed bytrituration in EtOAc, afforded the title compound as a white solid:ESI-MS: 496.9/498.9 [M+H]⁺; t_(R)=4.72 min (System 1); TLC: R_(f)=0.17(DCM/MeOH, 96:5).

Example 4 8-(2,6-Dichloro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylicacid (4-morpholin-4-yl-phenyl)-amide

The title compound was prepared in analogy to the procedure described inExample 1 but using N-(4-aminophenyl)-morpholine. Purification of thecrude product by silica gel column chromatography (DCM/MeOH, 97.5:2.5)afforded the title compound as a red solid: ESI-MS: 538.9/540.9 [M+H]⁺;t_(R)=4.61 min (System 1); TLC: R_(f)=0.15 (DCM/MeOH, 97.5:2.5).

Example 5 8-(2,6-Dichloro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylicacid [4-(2-dimethylamino-ethoxy)-phenyl]-amide

The title compound was prepared in analogy to the procedure described inExample 1 but using 4-(2-dimethylamino-ethoxy)-phenylamine (Step 5.1).Purification of the crude product by silica gel column chromatography(DCM/MeOH/NH₃ ^(aq), 96.5:2.5:1) afforded the title compound as a redsolid: ESI-MS: 540.8/542.7 [M+H]⁺; t_(R)=4.19 min (System 1); TLC:R_(f)=0.41 (DCM/MeOH/NH₃ ^(aq), 96.5:2.5:1).

Step 5.1: 4-(2-Dimethylamino-ethoxy)-phenylamine

1-Chloro-2-dimethylaminoethane hydrochloride (2 g, 21.9 mmol, 1.2 equiv)was added in one portion to a mixture of 4-aminophenol (2 g, 18.3 mmol)and finely powdered sodium hydroxide (1.8 g, 45.8 mmol, 2.5 equiv) inDMF (27 mL), under an argon atmosphere. The reaction mixture was stirredfor 17 h at rt. The resulting dark suspension was filtered. The filtratewas diluted with DCM (200 ml) and washed with brine (2×50 mL). Theorganic phase was dried (Na₂SO₄), filtered and concentrated.Purification of the residue by silica gel column chromatography(DCM/MeOH, 7:3) provided 3 g of the title compound as a brown solid:API-MS: 181.2 [M+H]⁺; TLC: R_(f)=0.18 (DCM/MeOH, 7:3).

Example 6 8-(2,6-Dichloro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylicacid (5-carbamoyl-pyridin-2-yl)-amide

The title compound was prepared in analogy to the procedure described inExample 1 but using 6-aminonicotinamide. Purification of the crudeproduct by silica gel column chromatography (DCM/MeOH, 97.5:2.5),followed by trituration in EtOAc, afforded the title compound as ayellow solid: ESI-MS: 497.9/499.9 [M+H]⁺; t_(R)=4.59 min (System 1);TLC: R_(f)=0.12 (DCM/MeOH, 97.5:2.5).

Example 7 8-(2,6-Dichloro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylicacid (4-hydroxy-phenyl)-amide

The title compound was prepared in analogy to the procedure described inExample 1 but using 4-aminophenol. Purification of the crude product bysilica gel column chromatography (DCM/MeOH, 95:5), followed bytrituration in DCM, afforded the title compound as a yellow solid:ESI-MS: 469.9/471.9 [M+H]⁺; t_(R)=4.71 min (System 1); TLC: R_(f)=0.44(DCM/MeOH, 95:5).

Example 8 8-(2,6-Dichloro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylicacid (4-piperazin-1-yl-phenyl)-amide

A mixture of4-(4-{[8-(2,6-dichloro-3,5-dimethoxy-phenyl)-quinoxaline-5-carbonyl]-amino}-phenyl)-piperazine-1-carboxylicacid tert-butyl ester (Step 8.1) (137 mg, 0.22 mmol) and a 4 N solutionof HCl in dioxane (5 mL) was stirred for 1 h at rt. The reaction mixturewas diluted with DCM and H₂O. The aqueous layer was separated andextracted with DCM. The organic phase was washed with H₂O and brine,dried (Na₂SO₄), filtered and concentrated. The residue was triturated inEt₂O to afford 95 mg of the title compound as a red solid: ESI-MS:537.9/539.9 [M+H]⁺; t_(R)=4.01 min (System 1).

Step 8.1:4-(4-{[8-(2,6-Dichloro-3,5-dimethoxy-phenyl)-quinoxaline-5-carbonyl]-amino}-phenyl)-piperazine-1-carboxylicacid tert-butyl ester

The title compound was prepared in analogy to the procedure described inExample 1 but using 4-(4-amino-phenyl)-piperazine-1-carboxylic acidtert-butyl ester (Step 8.2). After work-up with DCM and H₂O, triturationof the crude product in Et₂O afforded the title compound as a yellowsolid: ES-MS: 637.9/639.9 [M+H]⁺; t_(R)=5.31 min (System 1).

Step 8.2: 4-(4-Amino-phenyl)-piperazine-1-carboxylic acid tert-butylester

A suspension of 4-(4-nitro-phenyl)-piperazine-1-carboxylic acidtert-butyl ester (Step 8.3) (1.26 g, 4.1 mmol) and palladium on carbon(200 mg) in MeOH (30 mL) was stirred for 30 min at rt, under a hydrogenatmosphere. The reaction mixture was filtered through a pad of celiteand concentrated to afford 1.1 g of the title compound as a pink solid:ESI-MS: 278.2 [M+H]⁺; t_(R)=2.85 min (System 1).

Step 8.3: 4-(4-Nitro-phenyl)-piperazine-1-carboxylic acid tert-butylester

Di-tert-butyl-dicarbonate (1 M in THF, 5.8 mL, 5.8 mmol, 1.2 equiv) wasadded to a solution of 1-(4-nitro-phenyl)-piperazine (1 g, 4.8 mmol) andtriethylamine (1.0 mL, 7.2 mmol, 1.5 equiv) in THF (20 mL). The reactionmixture was stirred for 15 min at rt, quenched by addition of H₂O (0.5mL), and concentrated. The residue was diluted with EtOAc, washed with asaturated aqueous solution of NH₄Cl, H₂O and brine, dried (sodiumsulfate), filtered and concentrated. Trituration of the crude product inEt₂O afforded 1.26 g of the title compound as a yellow solid: ES-MS:308.1 [M+H]⁺; t_(R)=5.00 min (System 1).

Example 9 8-(2,6-Dichloro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylicacid [4-(4-methyl-piperazin-1-yl)-phenyl]-amide

The title compound was prepared in analogy to the procedure described inExample 1 but using 4-(4-methylpiperazin-1-yl)-aniline (WO2006000420).Title compound: ESI-MS: 551.8/553.9 [M+H]⁺; t_(R)=4.17 min (System 1).

Example 108-(2,6-Dichloro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid[4-(4-isopropyl-piperazin-1-yl)-phenyl]-amide

The title compound was prepared in analogy to the procedure described inExample 1 but using 4-(4-isopropylpiperazin-1-yl)-aniline(WO2006000420). Title compound: ESI-MS: 579.9/581.9 [M+H]⁺; t_(R)=4.37min (System 1).

Example 118-(2,6-Dichloro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid[4-(4-isopropyl-piperazin-1-ylmethyl)-phenyl]-amide

The title compound was prepared in analogy to the procedure described inExample 1 but using 4-(4-isopropyl-piperazin-1-ylmethyl)-phenylamine(Step 11.1). Title compound: ESI-MS: 593.8/595.8 [M+H]⁺; t_(R)=3.73 min(System 1).

Step 11.1: 4-(4-Isopropyl-piperazin-1-ylmethyl)-phenylamine

A suspension of 1-isopropyl-4-(4-nitro-benzyl)-piperazine (Step 11.2)(5.7 g, 21.65 mmol) and Raney Nickel (2 g) in MeOH (100 mL) was stirredfor 6 h at rt, under a hydrogen atmosphere. The reaction mixture wasfiltered through a pad of celite and concentrated to afford 4.9 g of thetitle compound as a white solid: ESI-MS: 234.2.

Step 11.2: 1-Isopropyl-4-(4-nitro-benzyl)-piperazine

A mixture of 4-nitrobenzylchloride (4.1 g, 23.90 mmol),N-isopropylpiperazine (3.6 g, 28.67 mmol, 1.2 equiv), potassiumcarbonate (6.5 g, 47.79 mmol, 2 equiv) and acetone (82 ml) was stirredfor 16 h at reflux. The reaction mixture was allowed to cool, was thenfiltered and concentrated. The residue was purified by silica gel columnchromatography (DCM/MeOH+1% NH₃ ^(aq), 9:1) to afford 5.7 g of the titlecompound: ESI-MS: 264.1 [M+H]⁺; TLC: t_(R)=1.73 min (System 1); TLC:R_(f)=0.34 (DCM/MeOH+1% NH₃ ^(aq), 9:1).

Example 128-(2,6-Dichloro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid[4-(4-ethyl-piperazin-1-ylmethyl)-phenyl]-amide

The title compound was prepared in analogy to the procedure described inExample 1 but using 4-(4-ethyl-piperazin-1-ylmethyl)-phenylamine. Titlecompound: ESI-MS: 579.8/581.8 [M+H]⁺; t_(R)=3.66 min (System 1).

Step 12.1: 4-(4-Ethyl-piperazin-1-ylmethyl)-phenylamine

The title compound was prepared in analogy to the procedure described inStep 11.1 but using 1-ethyl-4-(4-nitro-benzyl)-piperazine (Step 12.2):ESI-MS: 220.1 [M+H]⁺; TLC: R_(f)=0.08 (DCM/MeOH+1% NH₃ ^(aq), 9:1).

Step 12.2: 1-Ethyl-4-(4-nitro-benzyl)-piperazine

The title compound was prepared in analogy to the procedure described inStep 11.2. The title compound: ESI-MS: 250.1 [M+H]⁺; TLC: R_(f)=0.31(DCM/MeOH+1% NH₃ ^(aq), 9:1).

Example 138-(2,6-Dichloro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-amide

The title compound was prepared in analogy to the procedure described inExample 1 but using 4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine(WO2005047273). The title compound: ESI-MS: 566.8/568.8 [M+H]⁺;t_(R)=4.37 min (System 1).

Example 148-(2,6-Dichloro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid(1H-imidazol-2-yl)-amide

A mixture of8-(2,6-dichloro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid[1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-amide (Step 14.1)(0.527 g, 0.82 mmol), 5 N HCl (7 mL), and EtOH (4 mL) was stirred at 65°C. for 10 h. The reaction mixture was allowed to cool to rt, basified byaddition of a saturated aqueous solution of Na₂CO₃, and extracted withDCM. The combined organic phase was washed with H₂O and brine, dried(Na₂SO₄), filtered and concentrated. The residue was purified by silicagel column chromatography (DCM/MeOH/NH₃ ^(aq), 94:5:1) to afford 0.288 gof the title compound as a yellow solid: ESI-MS: 443.9/445.9 [M+H]⁺;t_(R)=3.74 min (System 1); TLC: R_(f)=0.30 (DCM/MeOH/NH₃ ^(aq), 94:5:1).

Step 14.1:8-(2,6-Dichloro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid[1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-amide

A mixture of8-(2,6-dichloro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid(Step 1.1) (0.400 g, 1.06 mmol),1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-ylamine (Step 14.2)(0.270 g, 1.27 mmol, 1.2 equiv), TBTU (408 mg, 1.27 mmol, 1.2 equiv),DIEA (0.74 mL, 4.23 mmol, 4.0 equiv) in DMF (5 mL) was stirred for 2 hat rt, diluted with EtOAc and H₂O, and extracted with EtOAc washed witha saturated aqueous solution of NaHCO₃, H₂O, and brine. The organicphase was washed with H₂O and brine, dried (Na₂SO₄), filtered andconcentrated. The residue was purified by silica gel columnchromatography (DCM/MeOH, 95:5) to afford 0.518 g of the title compoundas a yellow foam: ES-MS: 573.8/575.8 [M+H]⁺; t_(R)=5.03 min (System 1);R_(f)=0.19 (DCM₂/MeOH, 95:5).

Step 14.2: 1-(2-Trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-ylamine

A suspension of 2-nitro-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole(Step 14.3) (1.84 g, 7.57 mmol) and palladium on carbon (200 mg) in MeOH(30 mL) was stirred for 40 min at rt, under a hydrogen atmosphere. Thereaction mixture was filtered through a pad of celite and concentratedto afford 1.55 g of the title compound: ESI-MS: 214.1 [M+H]⁺; t_(R)=3.26min (System 1).

Step 14.3: 2-Nitro-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole

A suspension of 2-nitroimidazole (0.885 g, 7.8 mmol) and sodium hydride(60% dispersion in mineral oil, 0.440 g, 11.0 mmol, 1.4 equiv) in THF(20 mL) was stirred for 1.5 h at 5° C., under an argon atmosphere.2-(Trimethylsilyl)ethoxymethyl chloride (1.5 mL, 8.6 mmol, 1.1 equiv)was then added. The reaction mixture was stirred for 2.5 h at 5° C.,quenched by addition of a saturated aqueous solution of NH₄Cl, andextracted with EtOAc. The combined organic phase was washed with H₂O andbrine, dried (sodium sulfate), filtered and concentrated. The residuewas purified by silica gel column chromatography (Hex/EtOAc, 3:1) toafford 1.76 g of the title compound as a yellow oil: ES-MS: 244.1[M+H]⁺; t_(R)=4.63 min (System 1); TLC: R_(f)=0.19 (Hex/EtOAc, 3:1).

Example 158-(2,6-Dichloro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid(2H-pyrazol-3-yl)-amide

The title compound was prepared in analogy to the procedures describedin Example 14 but using 5-nitro-1H-pyrazole [Janssen, J. W. A. M.;Koeners, H. J.; Kruse, C. G.; Habrakern, Clarisse L. Gorlaeus Lab.,Univ. Leiden, Leiden, Neth. Journal of Organic Chemistry (1973), 38(10),1777-82] instead of 2-nitroimidazole in Step 14.3. The title compound:ESI-MS: 443.9/445.9 [M+H]⁺; t_(R)=4.42 min (System 1); TLC: R_(f)=0.22(DCM/MeOH/NH₃ ^(aq), 94:5:1).

Example 168-(2,6-Dichloro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid(3H-imidazol-4-yl)-amide

The title compound was prepared in analogy to the procedures describedin Example 14 but using 4-nitro-imidazole instead of 2-nitroimidazole inStep 14.3. The title compound: ESI-MS: 443.9/445.9 [M+H]⁺; t_(R)=3.66min (System 1); TLC: R_(f)=0.14 (DCM/MeOH/NH₃ ^(aq), 94:5:1).

Example 178-(2,6-Dichloro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid(4H-[1,2,4]triazol-3-yl)-amide

The title compound was prepared in analogy to the procedures describedin Example 14 but using 3-nitro-1,2,4-triazole instead of2-nitroimidazole in Step 14.3. Trituration of the crude product in DCMafforded the title compound: ESI-MS: 444.9/446.9 [M+H]⁺; t_(R)=4.24 min(System 1).

Example 188-(2,6-Dichloro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid(4-diethylaminomethyl-1H-imidazol-2-yl)-amide

The title compound was prepared in analogy to the procedures describedin Example 14 but using Raney nickel and MeOH/THF (1:1) instead ofpalladium on carbon and MeOH in Step 14.2,diethyl-(2-nitro-1H-imidazol-4-ylmethyl)-amine (Step 18.1) instead of2-nitroimidazole in Step 14.3. The title compound: ESI-MS: 443.9/445.9[M+H]⁺; t_(R)=4.42 min (System 1); TLC: R_(f)=0.22 (DCM/MeOH/NH₃ ^(aq),94:5:1).

Step 18.1: Diethyl-(2-nitro-1H-imidazol-4-ylmethyl)-amine

Formaldehyde (36% in H₂O, 1.0 mL, 13.3 mmol, 1.5 equiv) and diethylamine (0.92 mL, 8.8 mmol) were added sequentially to a suspension of2-nitro-imidazole (1 g, 8.8 mmol) in EtOH (20 mL). The resulting mixturewas heated to reflux for 18 h, allowed to cool to rt, and concentrated.Trituration of the residue in Et₂O afforded an impure sample of thetitle compound which was used without further purification.

Example 198-(2,6-Dichloro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid(4-pyrrolidin-1-ylmethyl-1H-imidazol-2-yl)-amide

The title compound was prepared in analogy to the procedures describedin Example 14 but using Raney nickel and MeOH/THF (1:1) instead ofpalladium on carbon and MeOH in Step 14.2,2-nitro-4-pyrrolidin-1-ylmethyl-1H-imidazole (Step 19.1) instead of2-nitroimidazole in Step 14.3. The title compound: ESI-MS: 526.9/528.9[M+H]⁺; t_(R)=3.48 min (System 1); TLC: R_(f)=0.30 (DCM/MeOH/NH₃ ^(aq),89:10:1).

Step 19.1: 2-Nitro-4-pyrrolidin-1-ylmethyl-1H-imidazole

The title compound was prepared in analogy to the procedure described inStep 18.1 but using pyrrolidine instead of diethyl amine, and it wasobtained as an impure sample which was used without furtherpurification.

Example 208-(2,6-Dichloro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid[4-(4-methyl-piperazin-1-ylmethyl)-1H-imidazol-2-yl]-amide

The title compound was prepared in analogy to the procedures describedin Example 14 but using Raney nickel and MeOH/THF (1:1) instead ofpalladium on carbon and MeOH in Step 14.2,1-methyl-4-(2-nitro-1H-imidazol-4-ylmethyl)-piperazine (Step 20.1)instead of 2-nitroimidazole in Step 14.3. The title compound: ESI-MS:555.8/557.8 [M+H]⁺; t_(R)=3.22 min (System 1).

Step 20.1: 1-Methyl-4-(2-nitro-1H-imidazol-4-ylmethyl)-piperazine

The title compound was prepared in analogy to the procedure described inStep 18.1 but using 1-methylpiperazine instead of diethyl amine, and itwas obtained as an impure sample which was used without furtherpurification.

Example 218-(2,6-Dichloro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid[4-(4-ethyl-piperazin-1-ylmethyl)-1H-imidazol-2-yl]-amide

The title compound was prepared in analogy to the procedures describedin Example 14 but using Raney nickel and MeOH/THF (1:1) instead ofpalladium on carbon and MeOH in Step 14.2,1-ethyl-4-(2-nitro-1H-imidazol-4-ylmethyl)-piperazine (Step 21.1)instead of 2-nitroimidazole in Step 14.3. The title compound: ESI-MS:569.8/571.8 [M+H]⁺; t_(R)=3.29 min (System 1).

Step 21.1: 1-Ethyl-4-(2-nitro-1H-imidazol-4-ylmethyl)-piperazine

The title compound was prepared in analogy to the procedure described inStep 18.1 but using 1-ethylpiperazine instead of diethyl amine, and itwas obtained as an impure sample which was used without furtherpurification.

Example 228-(2,6-Dichloro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid(4-dimethylaminomethyl-1H-imidazol-2-yl)-amide

The title compound was prepared in analogy to the procedures describedin Example 14 but using Raney nickel and MeOH/THF (1:1) instead ofpalladium on carbon and MeOH in Step 14.2,dimethyl-(2-nitro-1H-imidazol-4-ylmethyl)-amine (Step 22.2) instead of2-nitroimidazole in Step 14.3. The title compound: ESI-MS: 500.9/502.8[M+H]⁺; t_(R)=3.35 min (System 1); TLC: R_(f)=0.40 (DCM/MeOH/NH₃ ^(aq),89:10:1).

Step 22.1: Dimethyl-(2-nitro-1H-imidazol-4-ylmethyl)-amine

The title compound was prepared in analogy to the procedure described inStep 18.1 but using dimethyl amine instead of diethyl amine, and it wasobtained as an impure sample which was used without furtherpurification.

Example 238-(2,6-Dichloro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid(4-morpholin-4-ylmethyl-1H-imidazol-2-yl)-amide

The title compound was prepared in analogy to the procedures describedin Example 14 but using Raney nickel and MeOH/THF (1:1) instead ofpalladium on carbon and MeOH in Step 14.2,4-(2-nitro-1H-imidazol-4-ylmethyl)-morpholine (Step 23.1) instead of2-nitroimidazole in Step 14.3. The title compound: ESI-MS: 542.9/544.9[M+H]⁺; t_(R)=3.42 min (System 1); TLC: R_(f)=0.23 (DCM/MeOH/NH₃ ^(aq),89:10:1).

Step 23.1: 4-(2-Nitro-1H-imidazol-4-ylmethyl)-morpholine

The title compound was prepared in analogy to the procedure described inStep 18.1 but using morpholine instead of diethyl amine, and it wasobtained as an impure sample which was used without furtherpurification.

Example 248-(2,6-Dichloro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid(6-oxo-1,6-dihydro-pyridin-3-yl)-amide

The title compound was prepared in analogy to the procedure described inExample 1 but using 5-amino-pyridin-2-ol (Step 24.1) and stirring thereaction mixture for 40 h at rt. Title compound: ESI-MS: 470.8/472.8[M+H]⁺; t_(R)=4.28 min (System 1); TLC: R_(f)=0.17 (DCM/MeOH, 95:5).

Step 24.1: 5-Amino-pyridin-2-ol

A suspension of 2-hydroxy-5-nitropyridine (5 g, 35.7 mmol) and palladiumon carbon (500 mg) in MeOH (100 mL) was stirred for 1 h at rt, under ahydrogen atmosphere. The reaction mixture was filtered through a pad ofcelite and concentrated to afford 3.8 g of the title compound: ESI-MS:110.8 [M+H]⁺.

Example 258-(2,6-Dichloro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid[5-(4-methyl-piperazine-1-carbonyl)-pyridin-2-yl]amide

The title compound was prepared in analogy to the procedure described inStep 14.1 but using(6-amino-pyridin-3-yl)-(4-methyl-piperazin-1-yl)-methanone (Step 25.1)(2.4 equiv) and 2.4 equiv of TBTU. Title compound: ESI-MS: 580.8/582.8[M+H]⁺; t_(R)=3.86 min (System 1); TLC: R_(f)=0.29 (DCM/MeOH/NH₃ ^(aq),94:5:1).

Step 25.1: (6-Amino-pyridin-3-yl)-(4-methyl-piperazin-1-yl)-methanone

The title compound was prepared in analogy to the procedure described inStep 14.1 but using 6-amino-nicotinic acid and 1-methylpiperazine. Thereaction mixture was stirred overnight at 0° C. DCM was used fordilution and extraction instead of EtOAc. The dried organic phase wasconcentrated to afford an impure sample of the title compound which wasused without further purification.

Example 268-(2,6-Dichloro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid[5-(4-ethyl-piperazin-1-ylmethyl)-pyridin-2-yl]-amide

The title compound was prepared in analogy to the procedure described inStep 14.1 but using 2 equiv of5-(4-ethyl-piperazin-1-ylmethyl)-pyridin-2-ylamine (Step 26.1) andstirring the reaction mixture for 20 h at rt. Title compound: ESI-MS:580.8/582.8 [M+H]⁺; t_(R)=3.63 min (System 1); TLC: R_(f)=0.31(DCM/MeOH/NH₃ ^(aq), 94:5:1).

Step 26.1: 5-(4-Ethyl-piperazin-1-ylmethyl)-pyridin-2-ylaminehydrochloride

A mixture of [5-(4-ethyl-piperazin-1-ylmethyl)-pyridin-2-yl]carbamicacid tert-butyl ester (Step 26.2) (0.75 g, 2.8 mmol) and a 4 N solutionof HCl in dioxane (20 mL) was stirred for 72 h at rt and concentrated toafford 660 mg of the title compound as a white solid: ESI-MS: 221.1[M+H]⁺; t_(R)=0.80 min (System 1).

Step 26.2: [5-(4-Ethyl-piperazin-1-ylmethyl)-pyridin-2-yl]-carbamic acidtert-butyl ester

A mixture of methanesulfonic acid6-tert-butoxycarbonylamino-pyridin-3-ylmethyl ester (Step 26.3) (0.8 g,2.6 mmol), N-ethylpiperazine (0.37 mL, 2.9 mmol, 1.1 equiv), cesiumcarbonate (1 g, 3.2 mmol, 1.2 equiv), and DMF (10 ml) was stirred for 2h at rt, diluted with EtOAc and H₂O, and extracted with EtOAc. Theorganic phase was washed with H₂O and brine, dried (Na₂SO₄), filteredand concentrated to provide a yellow solid. Trituration in Et₂O afforded0.75 g of the title compound as a white solid: ES-MS: 321.2 [M+H]⁺.

Step 26.3: Methanesulfonic acid6-tert-butoxycarbonylamino-pyridin-3-ylmethyl ester

Methanesulfonic anhydride (0.854 g, 4.9 mmol, 1.1 equiv) was addedportionwise to a cold (5° C.) mixture of(5-hydroxymethyl-pyridin-2-yl)-carbamic acid tert-butyl ester (Step26.4) (1 g, 4.5 mmol) and triethylamine (0.75 mL, 5.4 mmol, 1.2 equiv)in DCM (20 mL), under an argon atmosphere. The reaction mixture wasallowed to stir for 1 h at 5° C., diluted with EtOAc and H₂O, andextracted with EtOAc. The organic phase was washed with H₂O and brine,dried (Na₂SO₄), filtered and concentrated to provide 1.25 g of the titlecompound as a white solid: t_(R)=2.60 min (System 1).

Step 26.4: (5-Hydroxymethyl-pyridin-2-yl)-carbamic acid tert-butyl

Lithium aluminium hydride (1.6 g, 40.9 mmol, 1.1 equiv) was addedportionwise to a cold (5° C.) solution of6-tert-butoxycarbonylamino-nicotinic acid ethyl ester (Step 26.5) (9.9g, 37.2 mmol) in THF (250 mL), under an argon atmosphere. The reactionmixture was stirred for 1 h at 5° C. and quenched by sequential additionof H₂O (4 mL), 15% NaOH aqueous solution (4 mL) and H₂O (12 mL). Theresulting mixture was filtered through a pad of celite and concentrated.The residue was diluted with EtOAc and H₂O, and extracted with EtOAc.The organic phase was washed with H₂O and brine, dried (Na₂SO₄),filtered and concentrated. The residue was purified by trituration inEt₂O to provide 5 g of the title compound as a white solid: ESI-MS:223.0 [M−H]⁻; t_(R)=1.75 min (System 1).

Step 26.5: 6-tert-Butoxycarbonylamino-nicotinic acid ethyl ester

A solution of di-tert-butyl dicarbonate (1.7 g, 7.8 mmol, 1.3 equiv) inCH₃CN (20 mL) is added dropwise to a suspension of ethyl6-aminonicotinate (1 g, 6.0 mmol) and DMAP (73 mg, 0.6 mmol, 0.1 equiv)in CH₃CN (10 mL) at rt. The reaction mixture was stirred for 4 h at rtand concentrated. The residue was diluted with EtOAc and H₂O, andextracted with EtOAc. The organic phase was washed with H₂O and brine,dried (Na₂SO₄), filtered and concentrated. The residue was purified bysilica gel column chromatography (Hex/EtOAc, 4:1) to afford 1.18 g ofthe title compound as a white solid: ES-MS: 265.1 [M−H]⁻; t_(R)=4.61 min(System 1); R_(f)=0.50 (Hex/EtOAc, 4:1).

Example 278-(2,6-Dichloro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid(5-diethylaminomethyl-pyridin-2-yl)-amide

The title compound was prepared in analogy to the procedure described inStep 14.1 but using 5-diethylaminomethyl-pyridin-2-ylamine (prepared asdescribed in Example 26 but using diethylamine in Step 26.2) andstirring the reaction mixture overnight at rt. Title compound: ESI-MS:539.9/541.8 [M+H]⁺; t_(R)=5.55 min (System 1); TLC: R_(f)=1.0(DCM/MeOH/NH₃ ^(aq), 89:10:1).

Example 288-(2,6-Dichloro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid(5-dimethylaminomethyl-pyridin-2-yl)-amide

The title compound was prepared in analogy to the procedure described inStep 14.1 but using 5-dimethylaminomethyl-pyridin-2-ylaminehydrochloride (prepared as described in Example 26 but usingdimethylamine hydrochloride in Step 26.2) and stirring the reactionmixture for 20 h at rt. Title compound: ESI-MS: 511.9/513.9 [M+H]⁺;t_(R)=3.96 min (System 1); TLC: R_(f)=0.56 (DCM/MeOH/NH₃ ^(aq), 91:8:1).

Example 298-(2,6-Dichloro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid(5-morpholin-4-ylmethyl-pyridin-2-yl)-amide

The title compound was prepared in analogy to the procedure described inStep 14.1 but using 5-morpholin-4-ylmethyl-pyridin-2-ylaminehydrochloride (prepared as described in Example 26 but using morpholinein Step 26.2) and stirring the reaction mixture for 18 h at rt. Titlecompound: ESI-MS: 553.9/555.8 [M+H]⁺; t_(R)=3.98 min (System 1); TLC:R_(f)=0.61 (DCM/MeOH/NH₃ ^(aq), 91:8:1).

Example 308-(2,6-Dichloro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid(5-pyrrolidin-1-ylmethyl-pyridin-2-yl)-amide

The title compound was prepared in analogy to the procedure described inStep 14.1 but using 5-pyrrolidin-1-ylmethyl-pyridin-2-ylaminehydrochloride (2 equiv, prepared as described in Example 26 but usingpyrrolidine in Step 26.2) and stirring the reaction mixture for 21 h atrt. Title compound: ESI-MS: 537.9/539.9 [M+H]⁺; t_(R)=4.16 min (System1); TLC: R_(f)=0.50 (DCM/MeOH/NH₃ ^(aq), 91:8:1).

Example 318-(2,6-Dichloro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid[5-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-yl]-amide

The title compound was prepared in analogy to the procedure described inStep 14.1 but using 5-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-ylaminehydrochloride (prepared as described in Example 26 but usingN-methylpiperazine in Step 26.2), 2.4 equiv of TBTU and stirring thereaction mixture for 22 h at rt. Title compound: ESI-MS: 566.8/568.8[M+H]⁺; t_(R)=3.62 min (System 1); TLC: R_(f)=0.41 (DCM/MeOH/NH₃ ^(aq),91:8:1).

Example 328-(2,6-Dichloro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid(4,5-bis-dimethylaminomethyl-1H-imidazol-2-yl)-amide

A mixture of formaldehyde (36% in H₂O, 60 μL, 0.84 mmol, 9.3 equiv),dimethyl amine (40% in H₂O, 66 μL, 0.54 mmol, 6 equiv) and8-(2,6-dichloro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid(1H-imidazol-2-yl)-amide (Example 14) (40 mg, 0.09 mmol) in n-butanol (2mL) was heated to reflux for 1.5 h, allowed to cool to rt, andconcentrated. The residue was diluted with DCM and an aqueous saturatedsolution of NaHCO₃. The layers were separated and the aqueous phase wasextracted with DCM. The combined organic phase was washed with brine,dried (Na₂SO₄), filtered and concentrated. The residue was purified bysilica gel column chromatography (DCM/MeOH/NH₃ ^(aq), 91:8:1), followedby trituration in Et₂O, to afford 9 mg of the title compound as a yellowsolid: ES-MS: 557.8/559.8 [M+H]⁺; t_(R)=3.15 min (System 1); TLC:R_(f)=0.09 (DCM/MeOH/NH₃ ^(aq), 91:8:1).

Example 338-(2,6-Dichloro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid[6-(4-isopropyl-piperazin-1-yl)-pyridin-3-yl]-amide

The title compound was prepared in analogy to the procedure described inStep 14.1 but using 6-(4-isopropyl-piperazin-1-yl)-pyridin-3-ylaniline(Step 33.1) and stirring the reaction mixture for 17 h at rt. Titlecompound: ESI-MS: 580.8/582.8 [M+H]⁺; t_(R)=3.75 min (System 1); TLC:R_(f)=0.37 (DCM/MeOH/NH₃ ^(aq), 94:5:1).

Step 33.1: 6-(4-Isopropyl-piperazin-1-yl)-pyridin-3-ylaniline

A mixture of 1-isopropyl-4-(4-nitro-phenyl)-piperazine (Step 33.2) (1.58g, 6.32 mmol), iron (1.4 g, 25.3 mmol, 4 equiv), EtOH (20 mL), H₂O (5mL) and AcOH (2.5 mL) was stirred for 2 h at 90° C. The reaction mixturewas allowed to cool to rt, basified by addition of aqueous NH₃, filteredthrough a pad of celite. The filtrate was concentrated (to remove EtOH),extracted with EtOAc and DCM, saturated with NaCl and extracted withDCM. The organic phase was washed with brine, dried (Na₂SO₄), filteredand concentrated. Purification of the residue by silica gel columnchromatography (DCM/MeOH/NH₃ ^(aq), 91:8:1) afforded 1.1 g of the titlecompound as a purple solid: ESI-MS: 221.1 [M+H]⁺; TLC: R_(f)=0.20(DCM/MeOH/NH₃ ^(aq), 91:8:1).

Step 33.2: 1-Isopropyl-4-(5-nitro-pyridin-2-yl)-piperazine

1-Isopropylpiperazine (1.8 mL, 12.7 mmol, 2 equiv) was added to a cold(5° C.) solution of 2-chloro-5-nitropyridine (1 g, 6.3 mmol) in DCM (5mL). The reaction mixture was allowed to warm to rt, stirred for 16 h,diluted with DCM and H₂O. The aqueous layer was separated and extractedwith DCM. The organic phase was washed with brine, dried (Na₂SO₄),filtered and concentrated to provide 1.58 g of the title compound as ayellow solid: ESI-MS: 251.2 [M+H]⁺; t_(R)=2.20 min.

Example 348-(2,6-Dichloro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid[6-(4-ethyl-piperazin-1-yl)-pyridin-3-yl]-amide

The title compound was prepared in analogy to the procedure described inStep 14.1 but using 6-(4-ethylpiperazin-1-yl)-pyridin-3-ylaniline(prepared as described in Example 33 but using N-ethyl-piperazine inStep 33.2) and stirring the reaction mixture for 72 h at rt. Titlecompound: ESI-MS: 566.8/568.8 [M+H]⁺; t_(R)=3.66 min (System 1); TLC:R_(f)=0.37 (DCM/MeOH/NH₃ ^(aq), 94:5:1).

Example 358-(2,6-Dichloro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid[2-(4-isopropyl-piperazin-1-yl)-pyrimidin-5-yl]amide

The title compound was prepared in analogy to the procedure described inStep 14.1 but using 2-(4-isopropyl-piperazin-1-yl)-pyrimidin-5-ylamine(Step 35.1) and stirring the reaction mixture for 72 h at rt. Titlecompound: ESI-MS: 581.7/583.7 [M+H]⁺; t_(R)=4.18 min (System 1); TLC:R_(f)=0.62 (DCM/MeOH/NH₃ ^(aq), 94:5:1).

Step 35.1: 2-(4-Isopropyl-piperazin-1-yl)-pyrimidin-5-ylamine

The title compound was prepared in analogy to the procedure described inStep 33.1 but using 2-(4-isopropyl-piperazin-1-yl)-5-nitro-pyrimidine(Step 35.2) and stirring the reaction mixture for 1.5 h. The titlecompound: ESI-MS: 222.1 [M+H]⁺; TLC: R_(f)=0.13 (DCM/MeOH/NH₃ ^(aq),94:5:1).

Step 35.2: 2-(4-Isopropyl-piperazin-1-yl)-5-nitro-pyrimidine

1-Isopropylpiperazine (1.8 mL, 12.7 mmol, 2 equiv) was added to a cold(5° C.) solution of 2-chloro-5-nitropyrimidine (1 g, 6.3 mmol) in DCM (5mL). The reaction mixture was stirred for 20 min at 5° C. and thendiluted with DCM and H₂O. The aqueous layer was separated and extractedwith DCM. The organic phase was washed with brine, dried (Na₂SO₄),filtered and concentrated to provide 1.41 g of the title compound as abeige solid: ESI-MS: 252.2 [M+H]⁺; t_(R)=1.89 min.

Example 368-(2,6-Dichloro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid[2-(4-ethyl-piperazin-1-yl)-pyrimidin-5-yl]-amide

The title compound was prepared in analogy to the procedure described inStep 14.1 but using 2-(4-ethyl-piperazin-1-yl)-pyrimidin-5-ylamine(prepared as described in Example 35 but using N-ethyl-piperazine inStep 35.2) and stirring the reaction mixture for 72 h at rt. Titlecompound: ESI-MS: 567.9/569.9 [M+H]⁺; t_(R)=4.11 min (System 1); TLC:R_(f)=0.56 (DCM/MeOH/NH₃ ^(aq), 94:5:1).

Example 378-(2,6-Dichloro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid{6-[methyl-(1-methyl-piperidin-4-yl)-amino]-pyridin-3-yl}-amide

The title compound was prepared in analogy to the procedure described inStep 14.1 but usingN-methyl-N-(1-methyl-piperidin-4-yl)-benzene-1,4-diamine [prepared asdescribed in Example 33 but using methyl-(1-methyl-piperidin-4-yl)-aminein Step 33.2 and stirring the corresponding reaction mixture for 15 h atrt] and stirring the reaction mixture for 3 days at rt. Title compound:ESI-MS: 581.0/583.2 [M+H]⁺; t_(R)=3.46 min (System 1); TLC: R_(f)=0.18(DCM/MeOH/NH₃ ^(aq), 94:5:1).

Example 388-(2,6-Dichloro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid{6-[(2-dimethylamino-ethyl)-methyl-amino]-pyridin-3-yl}-amide

The title compound was prepared in analogy to the procedure described inStep 14.1 but using5-amino-2-[N-(2-dimethylamino-ethyl)-N-methyl]-pyridine (prepared asdescribed in Example 33 but using N,N,N′-trimethyl-ethane-1,2-diamine inStep 33.2 and stirring the corresponding reaction mixture for 15 h atrt) and stirring the reaction mixture for 3 days at rt. Title compound:ESI-MS: 554.8/557.0 [M+H]⁺; t_(R)=3.58 min (System 1).

Example 398-(2,6-Dichloro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid[6-(4-methyl-piperazin-1-ylmethyl)-pyridin-3-yl]-amide

The title compound was prepared in analogy to the procedure described inStep 14.1 but using 6-(4-methyl-piperazin-1-ylmethyl)-pyridin-3-ylamine(Step 39.1), and stirring the reaction mixture for 3 h at rt. The crudeproduct was purified by trituration with Et₂O. Title compound: ESI-MS:566.9/569.1 [M+H]⁺; t_(R)=3.44 min (System 1).

Step 39.1: 6-(4-Methyl-piperazin-1-ylmethyl)-pyridin-3-ylamine

A suspension of 1-methyl-4-(5-nitro-pyridin-2-ylmethyl)-piperazine (Step39.2) (0.529 g, 2.24 mmol) and Raney nickel (0.1 g) in MeOH (10 mL) wasstirred for 1 h at rt, under a hydrogen atmosphere. The reaction mixturewas filtered through a pad of celite and concentrated to afford 0.448 gof the title compound as an off-white solid: ESI-MS: 207.2 [M+H]⁺.

Step 39.2: 1-Methyl-4-(5-nitro-pyridin-2-ylmethyl)-piperazine

Sodium triacetoxyborohydride (1.4 g, 6.6 mmol, 2 equiv) was addedportionwise to a cold (5° C.) solution of5-nitro-pyridine-2-carbaldehyde (Step 39.3) (0.5 g, 3.3 mmol) andN-methyl-piperazine (0.4 mL, 3.6 mmol, 1.1 equiv) in DCM (10 mL). Thereaction mixture was allowed to warm to rt, stirred for 16 h, dilutedwith DCM and saturated solution of NaHCO₃, and extracted with DCM. Theorganic phase was washed with H₂O and brine, dried (Na₂SO₄), filteredand concentrated. The residue was purified by silica gel columnchromatography (DCM/MeOH/NH₃ ^(aq), 91:8:1) to provide 0.532 g of thetitle compound as a yellow solid: ESI-MS: 237.2 [M+H]⁺; TLC: R_(f)=0.31(DCM/MeOH/NH₃ ^(aq), 91:8:1).

Step 39.3: 5-Nitro-pyridine-2-carbaldehyde

Diisobutylaluminium hydride (1 M in DCM, 44 mL, 44 mmol, 1.3 equiv) wasadded dropwise to a cold (−78° C.) solution of5-nitro-pyridine-2-carboxylic acid ethyl ester (step 39.4) (6.56 g, 33.5mmol) in DCM (130 mL), under an argon atmosphere. The reaction mixturewas allowed to warm to 5° C., quenched by addition of an aqueoussolution of potassium sodium tartrate, diluted with DCM and H₂O, stirredfor 16 h at rt, and filtered through a pad of celite. The filtrate wasextracted several times with DCM. The organic phase was washed with H₂Oand brine, dried (Na₂SO₄), filtered and concentrated. The residue waspurified by silica gel column chromatography (EtOAc/Hex, 1:1) to provide2.54 g of the title compound as a beige solid: ESI-MS: 151.1 [M−H]⁻.

Step 39.4: 5-Nitro-pyridine-2-carboxylic acid ethyl ester

A mixture of 5-nitro-pyridine-2-carboxylic acid (Step 39.5) (5.74 g,34.2 mmol), H₂SO₄ (1 mL) and EtOH (50 mL) was stirred for 1.5 h atreflux. The residue was diluted with EtOAc and saturated solution ofNaHCO₃. The aqueous layer was separated and extracted with EtOAc. Theorganic phase was washed with H₂O and brine, dried (Na₂SO₄), filteredand concentrated to afford 6.1 g of the title compound as a white solid:ES-MS: 197.1 [M+H]⁺; t_(R)=3.22 min (System 1).

Step 39.5: 5-Nitro-pyridine-2-carboxylic acid

A mixture of 2-bromo-5-nitro-pyridine (5.8 g, 28.6 mmol) and CuCN (3.3g, 37.1 mmol, 1.3 equiv) in DMF (50 mL) was stirred at reflux for 15min, under an argon atmosphere. The reaction mixture was allowed to coolto rt, diluted with Et₂O and H₂O. The aqueous layer was separated andextracted with Et₂O. The organic phase was washed with brine, dried(Na₂SO₄), filtered and concentrated. The residue was treated with 6N HCl(50 mL) for 1.5 h at reflux. The mixture was poured onto H₂O (200 mL).The resulting white solid was collected by vacuum filtration and driedto provide 3.1 g of the title compound: ESI-MS: 167.0 [M−H]⁻; t_(R)=1.59min.

Example 408-(2,6-Dichloro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid[6-(4-ethyl-piperazin-1-ylmethyl)-pyridin-3-yl]-amide

The title compound was prepared in analogy to the procedure described inStep 14.1 but using 6-(4-ethyl-piperazin-1-ylmethyl)-pyridin-3-ylamine(prepared as described in Example 39 but using N-ethyl-piperazine inStep 39.2), and stirring the reaction mixture for 16 h at rt. The crudeproduct was purified by trituration with Et₂O. Title compound: ESI-MS:580.9/583.1 [M+H]⁺; t_(R)=3.53 min (System 1).

Example 418-(2,6-Dichloro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid(6-pyrrolidin-1-ylmethyl-pyridin-3-yl)-amide

The title compound was prepared in analogy to the procedure described inStep 14.1 but using 6-pyrrolidin-1-ylmethyl-pyridin-3-ylamine (preparedas described in Example 39 but using pyrrolidine in Step 39.2), andstirring the reaction mixture for 1 h at rt. Title compound: ESI-MS:538.0/540.1 [M+H]⁺; t_(R)=4.22 min (System 1); TLC: R_(f)=0.35(DCM/MeOH/NH₃ ^(aq), 94:5:1).

Example 428-(2,6-Dichloro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid(6-diethylaminomethyl-pyridin-3-yl)-amide

The title compound was prepared in analogy to the procedure described inStep 14.1 but using 6-diethylaminomethyl-pyridin-3-ylamine (prepared asdescribed in Example 39 but using diethylamine in Step 39.2), andstirring the reaction mixture for 18 h at rt. The crude product waspurified by trituration with Et₂O. Title compound: ESI-MS: 540.0/542.1[M+H]⁺; t_(R)=4.30 min (System 1).

Example 438-(2,6-Dichloro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid(6-morpholin-4-ylmethyl-pyridin-3-yl)-amide

The title compound was prepared in analogy to the procedure described inStep 14.1 but using 6-morpholin-4-ylmethyl-pyridin-3-ylamine (preparedas described in Example 39 but using morpholine in Step 39.2), andstirring the reaction mixture for 18 h at rt. The crude product waspurified by trituration with Et₂O. Title compound: ESI-MS: 553.9/556.1[M+H]⁺; t_(R)=4.30 min (System 1).

Example 44 8-(2-Fluoro-phenyl)-quinoxaline-5-carboxylic acid[4-(2-dimethylamino-ethoxy)-phenyl]-amide

The title compound was prepared in analogy to the procedure described inStep 14.1 but stirring the reaction mixture overnight and using4-(2-dimethylamino-ethoxy)-phenylamine (Step 5.1) and8-(2-fluoro-phenyl)-quinoxaline-5-carboxylic acid. The latter compoundwas prepared as described in Steps 1.2-1.7 but using2-fluorophenylboronic acid in Step 1.4. Title compound: ESI-MS: 431.0[M+H]⁺; t_(R)=3.93 min (System 1); TLC: R_(f)=0.29 (DCM/MeOH/NH₃ ^(aq),96:3:1).

Example 45 8-(2-Fluoro-phenyl)-quinoxaline-5-carboxylic acid(1H-imidazol-2-yl)-amide

The title compound was prepared in analogy to the procedure described inExample 14 but using 8-(2-fluoro-phenyl)-quinoxaline-5-carboxylic acid(Example 44) in Step 14.1. Title compound: ESI-MS: 334.0 [M+H]⁺;t_(R)=3.39 min (System 1); TLC: R_(f)=0.54 (DCM/MeOH, 9:1).

Example 46 8-Naphthalen-1-yl-quinoxaline-5-carboxylic acid[4-(4-methyl-piperazin-1-yl)-phenyl]-amide

The title compound was prepared in analogy to the procedure described inin Step 14.1 but stirring the reaction mixture overnight and using4-(4-methylpiperazin-1-yl)-aniline (WO2006000420) and8-naphthalen-1-yl-quinoxaline-5-carboxylic acid. The latter compound wassynthesized as described in Steps 1.2-1.7 but using 1-naphtylboronicacid in Step 1.4. Title compound: ESI-MS: 474.0 [M+H]⁺; t_(R)=4.34 min(System 1); TLC: R_(f)=0.45 (DCM/MeOH/NH₃ ^(aq), 94:5:1).

Example 47 8-Naphthalen-1-yl-quinoxaline-5-carboxylic acid(5-diethylaminomethyl-pyridin-2-yl)-amide

The title compound was prepared in analogy to the procedure described inStep 14.1 but stirring the reaction mixture overnight and using5-diethylaminomethyl-pyridin-2-ylamine (Example 27) and8-naphthalen-1-yl-quinoxaline-5-carboxylic acid (Example 46). Titlecompound: ESI-MS: 462.0 [M+H]⁺; t_(R)=4.35 min (System 1); TLC:R_(f)=0.72 (DCM/MeOH/NH₃ ^(aq), 91:8:1).

Example 48 8-Naphthalen-1-yl-quinoxaline-5-carboxylic acid[5-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-yl]-amide

The title compound was prepared in analogy to the procedure described inStep 14.1 but stirring the reaction mixture for 72 h at rt and using 3equiv of 5-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-ylaminehydrochloride (Example 31), TBTU (2.4 equiv) and8-naphthalen-1-yl-quinoxaline-5-carboxylic acid (Example 46). Titlecompound: ESI-MS: 489.1 [M+H]⁺; t_(R)=3.73 min (System 1); TLC:R_(f)=0.08 (DCM/MeOH, 9:1).

Example 49 8-Naphthalen-1-yl-quinoxaline-5-carboxylic acid(1H-imidazol-2-yl)-amide

The title compound was prepared in analogy to the procedures describedin Example 14 but using 8-naphthalen-1-yl-quinoxaline-5-carboxylic acid(Example 46). Title compound: ESI-MS: 366.1 [M+H]⁺; t_(R)=3.88 min(System 1); TLC: R_(f)=0.43 (DCM/MeOH, 9:1).

Example 50 8-Naphthalen-1-yl-quinoxaline-5-carboxylic acid[6-(4-methyl-piperazin-1-yl)-Pyridin-3-yl]-amide

The title compound was prepared in analogy to the procedure described inStep 14.1 but stirring the reaction mixture for 20 h at rt and using6-(4-methylpiperazin-1-yl)-pyridin-3-ylamine (prepared as described inExample 33 but using N-methyl-piperazine in Step 33.2) and8-naphthalen-1-yl-quinoxaline-5-carboxylic acid (Example 46). Titlecompound: ESI-MS: 475.0 [M+H]⁺; t_(R)=3.76 min (System 1).

Example 51 8-Naphthalen-1-yl-quinoxaline-5-carboxylic acid[4-(4-methyl-piperazin-1-ylmethyl)-1H-imidazol-2-yl]-amide

The title compound was prepared in analogy to the procedures describedin Example 14 but using 8-naphthalen-1-yl-quinoxaline-5-carboxylic acid(Example 46) in Step 14.1, Raney nickel and MeOH/THF (1:1) instead ofpalladium on carbon and MeOH in Step 14.2 and1-methyl-4-(2-nitro-1H-imidazol-4-ylmethyl)-piperazine (Step 20.1)instead of 2-nitroimidazole in Step 14.3. Title compound: ESI-MS: 478.1[M+H]⁺; t_(R)=3.36 min (System 1); TLC: R_(f)=0.15 (DCM/MeOH, 9:1).

Example 52 8-Isoquinolin-4-yl-quinoxaline-5-carboxylic acid[3-(4-ethyl-piperazin-1-yl)-phenyl]-amide

The title compound was prepared in analogy to the procedure described inStep 14.1 but using 3-(4-ethylpiperazin-1-yl)-aniline (Step 2.1) and8-isoquinolin-4-yl-quinoxaline-5-carboxylic acid. The latter compoundwas synthesized as described in Steps 1.2-1.7 but using4-isoquinolineboronic acid in Step 1.4. Title compound: ESI-MS: 489.2[M+H]⁺; t_(R)=11.28 min (System 2).

Example 53 8-Isoquinolin-4-yl-quinoxaline-5-carboxylic acid[4-(4-ethyl-piperazin-1-yl)-phenyl]-amide

The title compound was prepared in analogy to the procedure described inStep 14.1 but using 4-(4-ethylpiperazin-1-yl)-aniline (Step 1.9) and8-isoquinolin-4-yl-quinoxaline-5-carboxylic acid (Example 52). Titlecompound: ESI-MS: 489.1 [M+H]⁺; t_(R)=10.58 min (System 2).

Example 54 8-Isoquinolin-4-yl-quinoxaline-5-carboxylic acid[4-(2-dimethylamino-ethoxy)-phenyl]-amide

The title compound was prepared in analogy to the procedure described inStep 14.1 but using 4-(2-dimethylamino-ethoxy)-phenylamine (Step 5.1)and 8-isoquinolin-4-yl-quinoxaline-5-car-boxylic acid (Example 52).Title compound: ESI-MS: 464.1 [M+H]⁺; t_(R)=8.23 min (System 2).

Example 55 8-Isoquinolin-4-yl-quinoxaline-5-carboxylic acid(1H-imidazol-2-yl)-amide

The title compound was prepared in analogy to the procedures describedin Example 14 but using 8-isoquinolin-4-yl-quinoxaline-5-carboxylic acid(Example 52) in Step 14.1. Title compound: ESI-MS: 367.0 [M+H]⁺; TLC:R_(f)=0.17 (DCM/MeOH, 95:5).

Example 56 8-Isoquinolin-4-yl-quinoxaline-5-carboxylic acid[5-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-yl]-amide

The title compound was prepared in analogy to the procedure described inStep 14.1 but stirring the reaction mixture for 17 h at rt, using 2equiv of 5-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-ylaminehydrochloride (Example 31), TBTU (2 equiv) and8-isoquinolin-4-yl-quinoxaline-5-carboxylic acid (Example 52). Titlecompound: ESI-MS: 490.0 [M+H]⁺; t_(R)=2.21 min (System 1); TLC:R_(f)=0.17 (DCM/MeOH, 9:1).

Example 57 8-Isoquinolin-4-yl-quinoxaline-5-carboxylic acid[6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-amide

The title compound was prepared in analogy to the procedure described inStep 14.1 but stirring the reaction mixture for 20 h at rt and using6-(4-methylpiperazin-1-yl)-pyridin-3-ylamine (prepared as described inExample 33 but using N-methyl-piperazine in Step 33.2) and8-isoquinolin-4-yl-quinoxaline-5-carboxylic acid (Example 52). Titlecompound: ESI-MS: 476.1 [M+H]⁺; t_(R)=1.98 min (System 1).

Example 58 8-Isoquinolin-4-yl-quinoxaline-5-carboxylic acid[4-(4-methyl-piperazin-1-ylmethyl)-1H-imidazol-2-yl]-amide

The title compound was prepared in analogy to the procedures describedin Example 14 but using1-methyl-4-(2-nitro-1H-imidazol-4-ylmethyl)-piperazine (Step 20.1)instead of 2-nitroimidazole in Step 14.3, Raney nickel and MeOH/THF(1:1) instead of palladium on carbon and MeOH in Step 14.2, and8-isoquinolin-4-yl-quinoxaline-5-carboxylic acid (Example 52) in Step14.1. Title compound: ESI-MS: 479.0 [M+H]⁺; TLC: R_(f)=0.16 (DCM/MeOH,9:1).

Example 59 8-Benzo[b]thiophen-3-yl-quinoxaline-5-carboxylic acid[5-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-yl]-amide

The title compound was prepared in analogy to the procedure described inStep 14.1 but stirring the reaction mixture at rt overnight and using 2equiv of 5-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-ylaminehydrochloride (Example 31), TBTU (2 equiv) and8-benzo[b]thiophen-3-yl-quinoxaline-5-carboxylic acid. The carboxylicacid was synthesized as described in Steps 1.2-1.7 but usingbenzothiophene-3-boronic acid in Step 1.4. Title compound: ESI-MS: 494.9[M+H]⁺; t_(R)=3.77 min (System 1); TLC: R_(f)=0.17 (DCM/MeOH, 9:1).

Example 60 8-Benzo[b]thiophen-3-yl-quinoxaline-5-carboxylic acid(1H-imidazol-2-yl)-amide

The title compound was prepared in analogy to the procedures describedin Example 14 but using 8-benzo[b]thiophen-3-yl-quinoxaline-5-carboxylicacid (Example 59) in Step 14.1. Title compound: ESI-MS: 372.0 [M+H]⁺;t_(R)=3.88 min (System 1); TLC: R_(f)=0.57 (DCM/MeOH, 9:1).

Example 61 8-Benzo[b]thiophen-3-yl-quinoxaline-5-carboxylic acid[6-(4-methyl-piperazin-1-YD-Pyridin-3-yl]-amide

The title compound was prepared in analogy to the procedure described inStep 14.1 but stirring the reaction mixture for 20 h at rt, using6-(4-methylpiperazin-1-yl)-pyridin-3-ylamine (prepared as described inExample 33 but using N-methyl-piperazine in Step 33.2) and8-benzo[b]thiophen-3-yl-quinoxaline-5-carboxylic acid (Example 59).Title compound: ESI-MS: 481.0 [M+H]⁺; t_(R)=3.81 min (System 1); TLC:R_(f)=0.40 (DCM/MeOH, 9:1).

Example 62 8-Benzo[b]thiophen-3-yl-quinoxaline-5-carboxylic acid[4-(4-methyl-piperazin-1-ylmethyl)-1H-imidazol-2-yl]-amide

The title compound was prepared in analogy to the procedures describedin Example 14 but stirring the reaction mixture for 20 h at 65° C.,using 1-methyl-4-(2-nitro-1H-imidazol-4-ylmethyl)-piperazine (Step 20.1)instead of 2-nitroimidazole in Step 14.3, Raney nickel and MeOH/THF(1:1) instead of palladium on carbon and MeOH in Step 14.2, and8-benzo[b]thiophen-3-yl-quinoxaline-5-carboxylic acid (Example 59) inStep 14.1. Title compound: ESI-MS: 484.0 [M+H]⁺; t_(R)=3.36 min (System1); TLC: R_(f)=0.10 (DCM/MeOH, 9:1).

Example 63 8-(2-Chloro-5-methoxy-phenyl)-quinoxaline-5-carboxylic acid[3-(4-ethyl-piperazin-1-yl)-phenyl]-amide

The title compound was prepared in analogy to the procedure described inStep 14.1 but using 3-(4-ethylpiperazin-1-yl)-aniline (Step 2.1) and8-(2-chloro-5-methoxy-phenyl)-quinoxaline-5-carboxylic acid. The lattercompound was synthesized as described in Steps 1.2-1.7 but using2-chloro-4-methoxyphenylboronic acid in Step 1.4. Title compound:ESI-MS: 502.1 [M]⁺; t_(R)=3.57 min (System 3).

Example 64 8-(2-Chloro-5-methoxy-phenyl)-quinoxaline-5-carboxylic acid[4-(4-ethyl-piperazin-1-yl)-phenyl]-amide

The title compound was prepared in analogy to the procedure described inStep 14.1 but using 4-(4-ethylpiperazin-1-yl)-aniline (Step 1.9) and8-(2-chloro-5-methoxy-phenyl)-quinoxaline-5-carboxylic acid (Example63). Title compound: ESI-MS: 502.1 [M]⁺; t_(R)=3.50 min (System 3).

Example 65 8-(2-Chloro-5-methoxy-phenyl)-quinoxaline-5-carboxylic acid[4-(2-dimethylamino-ethoxy)-phenyl]-amide

The title compound was prepared in analogy to the procedure described inStep 14.1 but using 4-(2-dimethylamino-ethoxy)-phenylamine (Step 5.1)and 8-(2-chloro-5-methoxy-phenyl)-quinoxaline-5-carboxylic acid (Example63). Title compound: ESI-MS: 476.9 [M]⁺; t_(R)=3.43 min (System 3).

Example 66 8-(2-Chloro-5-methoxy-phenyl)-quinoxaline-5-carboxylic acid(1H-imidazol-2-yl)-amide

The title compound was prepared in analogy to the procedures describedin Example 14 but using8-(2-chloro-5-methoxy-phenyl)-quinoxaline-5-carboxylic acid (Example 63)in Step 14.1. Title compound: ESI-MS: 380.0 [M+H]⁺; t_(R)=3.61 min(System 1); TLC: R_(f)=0.36 (DCM/MeOH, 95:5).

Example 67 8-(4-Methyl-thiophen-3-yl)-quinoxaline-5-carboxylic acid[5-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-yl]-amide

The title compound was prepared in analogy to the procedure described inStep 14.1 but stirring the reaction mixture at rt overnight, using 2equiv of 5-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-ylaminehydrochloride (Example 31), TBTU (2 equiv) and8-(4-methyl-thiophen-3-yl)-quinoxaline-5-carboxylic acid. The carboxylicacid was synthesized as described in Steps 1.2-1.7 but using4-methyl-3-thiopheneboronic acid in Step 1.4. Title compound: ESI-MS:459.1 [M+H]⁺; t_(R)=3.41 min (System 1); TLC: R_(f)=0.25 (DCM/MeOH,9:1).

Example 68 8-(4-Methyl-thiophen-3-yl)-quinoxaline-5-carboxylic acid[6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-amide

The title compound was prepared in analogy to the procedure described inStep 14.1 but stirring the reaction mixture for 20 h at rt, using6-(4-methylpiperazin-1-yl)-pyridin-3-ylamine (prepared as described inExample 33 but using N-methyl-piperazine in Step 33.2) and8-(4-methyl-thiophen-3-yl)-quinoxaline-5-carboxylic acid (Example 67).Title compound: ESI-MS: 445.0 [M+H]⁺; t_(R)=3.42 min (System 1).

Example 69 8-(4-Methyl-thiophen-3-yl)-quinoxaline-5-carboxylic acid[4-(4-methyl-piperazin-1-ylmethyl)-1H-imidazol-2-yl]-amide

The title compound was prepared in analogy to the procedures describedin Example 14 but stirring the reaction mixture for 16 h at 60° C.,using 1-methyl-4-(2-nitro-1H-imidazol-4-ylmethyl)-piperazine (Step 20.1)instead of 2-nitroimidazole in Step 14.3, Raney nickel and MeOH/THF(1:1) instead of palladium on carbon and MeOH in Step 14.2, and8-(4-methyl-thiophen-3-yl)-quinoxaline-5-carboxylic acid (Example 67) inStep 14.1. Title compound: ESI-MS: 448.0 [M+H]⁺; t_(R)=3.00 min (System1); TLC: R_(f)=0.14 (DCM/MeOH, 9:1).

Example 70 8-(4-Methyl-thiophen-3-yl)-quinoxaline-5-carboxylic acid(1H-imidazol-2-yl)-amide

The title compound was prepared in analogy to the procedures describedin Example 14 but using8-(4-methyl-thiophen-3-yl)-quinoxaline-5-carboxylic acid (Example 67) inStep 14.1. Title compound: ESI-MS: 336.1 [M+H]⁺; t_(R)=3.47 min (System1); TLC: R_(f)=0.66 (DCM/MeOH, 9:1).

Example 71 8-(2,6-Dimethyl-phenyl)-quinoxaline-5-carboxylic acid[3-(4-ethyl-piperazin-1-yl)-phenyl]-amide

The title compound was prepared in analogy to the procedure described inStep 14.1 but using 3-(4-ethylpiperazin-1-yl)aniline (Step 2.1) and8-(2,6-dimethyl-phenyl)-quinoxaline-5-carboxylic acid. The carboxylicacid was synthesized as described in Steps 1.2-1.7 but using2,6-dimethylphenylboronic acid and Pd(PPh₃)₄ in Step 1.4. Titlecompound: ESI-MS: 466.2 [M+H]⁺; t_(R)=3.74 min (System 3).

Example 72 8-(2,6-Dimethyl-phenyl)-quinoxaline-5-carboxylic acid[4-(4-ethyl-piperazin-1-yl)-phenyl]-amide

The title compound was prepared in analogy to the procedure described inStep 14.1 but using 4-(4-ethylpiperazin-1-yl)aniline (Step 1.9) and8-(2,6-dimethyl-phenyl)-quinoxaline-5-carboxylic acid (Example 71).Title compound: ESI-MS: 466.2 [M+H]⁺; t_(R)=3.67 min (System 3).

Example 73 8-(2,6-Dimethyl-phenyl)-quinoxaline-5-carboxylic acid[4-(2-dimethylamino-ethoxy)-phenyl]-amide

The title compound was prepared in analogy to the procedure described inStep 14.1 but using 4-(2-dimethylamino-ethoxy)-phenylamine (Step 5.1)and 8-(2,6-dimethyl-phenyl)-quinoxaline-5-carboxylic acid (Example 71).Title compound: ESI-MS: 441.1 [M+H]⁺; t_(R)=3.52 min (System 3).

Example 74 8-(2,6-Dimethyl-phenyl)-quinoxaline-5-carboxylic acid(1H-imidazol-2-yl)-amide

The title compound was prepared in analogy to the procedures describedin Example 14 but using 8-(2,6-dimethyl-phenyl)-quinoxaline-5-carboxylicacid (Example 71) in Step 14.1. Title compound: ESI-MS: 344.1 [M+H]⁺;t_(R)=3.62 min (System 1); TLC: R_(f)=0.50 (DCM/MeOH, 95:5).

Example 75 8-(2,6-Dimethyl-phenyl)-quinoxaline-5-carboxylic acid[5-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-yl]-amide

The title compound was prepared in analogy to the procedure described inStep 14.1 but stirring the reaction mixture for 2 days at rt, using 2equiv of 5-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-ylaminehydrochloride (Example 31), TBTU (2 equiv) and8-(2,6-dimethyl-phenyl)-quinoxaline-5-carboxylic acid (Example 71).Title compound: ESI-MS: 467.1 [M+H]⁺; t_(R)=3.55 min (System 1); TLC:R_(f)=0.15 (DCM/MeOH, 9:1).

Example 76 8-(2,6-Dimethyl-phenyl)-quinoxaline-5-carboxylic acid[6-(4-methyl-piperazin-1-O-Pyridin-3-yl]-amide

The title compound was prepared in analogy to the procedure described inStep 14.1 but stirring the reaction mixture for 20 h at rt, using6-(4-methylpiperazin-1-yl)-pyridin-3-ylamine (prepared as described inExample 33 but using N-methyl-piperazine in Step 33.2) and8-(2,6-dimethyl-phenyl)-quinoxaline-5-carboxylic acid (Example 71).Title compound: ESI-MS: 453.1 [M+H]⁺; t_(R)=3.55 min (System 1).

Example 77 8-(2,6-Dimethyl-phenyl)-quinoxaline-5-carboxylic acid[4-(4-methyl-piperazin-1-ylmethyl)-1H-imidazol-2-yl]-amide

The title compound was prepared in analogy to the procedures describedin Example 14 but stirring the reaction mixture for at 60° C. overnight,using 1-methyl-4-(2-nitro-1H-imidazol-4-ylmethyl)-piperazine (Step 20.1)instead of 2-nitroimidazole in Step 14.3 and8-(2,6-dimethyl-phenyl)-quinoxaline-5-carboxylic acid (Example 71), andusing Raney nickel and MeOH/THF (1:1) instead of palladium on carbon andMeOH in Step 14.2. Title compound: ESI-MS: 456.1 [M+H]⁺; t_(R)=3.18 min(System 1); TLC: R_(f)=0.15 (DCM/MeOH, 9:1).

Example 788-(2,6-Dichloro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acidpyridin-3-ylamide

The title compound was prepared in analogy to the procedure described inStep 14.1 but using 3-aminopyridine and stirring the reaction mixturefor 16 h at rt. Title compound: ESI-MS: 455.0/456.9 [M+H]⁺; t_(R)=3.76min (System 1); TLC: R_(f)=0.35 (DCM/MeOH/NH₃ ^(aq), 96:3:1).

Example 798-(2,6-Dichloro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acidpyridin-2-ylamide

The title compound was prepared in analogy to the procedure described inStep 14.1 but using 2-aminopyridine (2 equiv), TBTU (4 equiv) andstirring the reaction mixture for 16 h at rt. Title compound: ESI-MS:455.0/456.9 [M+H]⁺; t_(R)=4.47 min (System 1); TLC: R_(f)=0.61(DCM/MeOH/NH₃ ^(aq), 96:3:1).

Example 808-(2,6-Dichloro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid(5-methyl-pyridin-2-yl)-amide

The title compound was prepared in analogy to the procedure described inStep 14.1 but using 2-amino-5-methylpyridine (2 equiv), TBTU (4 equiv)and stirring the reaction mixture for 4 days at rt. Title compound:ESI-MS: 469.0/470.9 [M+H]⁺; t_(R)=4.48 min (System 1).

Example 818-(2,6-Dichloro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid(5-{[(2-dimethylamino-ethyl)-methyl-amino]-methyl}-pyridin-2-yl)-amide

The title compound was prepared in analogy to the procedure described inStep 14.1 but usingN-(6-amino-pyridin-3-ylmethyl)-N,N′,N′-trimethyl-ethane-1,2-diamine(prepared as described in Example 26 but usingN,N,N′-trimethyl-ethane-1,2-diamine in Step 26.2) and stirring thereaction mixture for 4 days at rt. Title compound: ESI-MS: 569.0/571.2[M+H]⁺; t_(R)=3.44 min (System 1); TLC: R_(f)=0.19 (DCM/MeOH/NH₃ ^(aq),94:5:1).

Example 828-(2,6-Dichloro-3,5-dimethoxy-phenyl)-3-(4-ethyl-piperazin-1-ylmethyl)-quinoxaline-5-carboxylicacid pyridin-3-ylamide

The title compound was prepared in analogy to the procedure described inStep 14.1 but using 3-aminopyridine,8-(2,6-dichloro-3,5-dimethoxy-phenyl)-3-(4-ethyl-piperazin-1-ylmethyl)-quinoxaline-5-carboxylicacid (Step 82.1) and stirring the reaction mixture for 12 h at rt. Titlecompound: ESI-MS: 581.0/583.2 [M+H]⁺; t_(R)=3.24 min (System 1); TLC:R_(f)=0.38 (DCM/MeOH, 9:1).

Step 82.1:8-(2,6-Dichloro-3,5-dimethoxy-phenyl)-3-(4-ethyl-piperazin-1-ylmethyl)-quinoxaline-5-carboxylicacid

A solution of KOH (0.818 g, 14.6 mmol, 10 equiv) in H₂O (20 mL) wasadded to 710 mg (1.46 equiv) of a mixture of8-(2,6-dichloro-3,5-dimethoxy-phenyl)-3-(4-ethyl-piperazin-1-ylmethyl)-quinoxaline-5-carbonitrileand8-(2,6-dichloro-3,5-dimethoxy-phenyl)-2-(4-ethyl-piperazin-1-ylmethyl)-quinoxaline-5-carbonitrile(Step 82.2) (710 mg, 1.46 mmol) in ethylene glycol (20 mL). The reactionmixture was stirred at 150° C. for 3 h, allowed to cool to rt and washedwith EtOAc (2×100 mL). The aqueous layer was acidified to pH 3-4 byaddition of 1N HCl. The resulting suspension was filtered. The filtratecontains8-(2,6-dichloro-3,5-dimethoxy-phenyl)-2-(4-ethyl-piperazin-1-ylmethyl)-quinoxaline-5-carboxylicacid (Step 83.1). The residue in the filter was triturated in 1N HCl (3mL) and filtered. The filtrate was basified to pH 5 and extracted withDCM (2×100 mL). The organic layer was dried (Na₂SO₄), filtered andconcentrated to afford 190 mg of the title compound as a white solid:ES-MS: 505.0/506.6 [M+H]⁺; t_(R)=3.46 min (System 1).

Step 82.2:8-(2,6-Dichloro-3,5-dimethoxy-phenyl)-3-(4-ethyl-piperazin-1-ylmethyl)-quinoxaline-5-carbonitrileand8-(2,6-dichloro-3,5-dimethoxy-phenyl)-2-(4-ethyl-piperazin-1-ylmethyl)-quinoxaline-5-carbonitrile

N-Ethylpiperazine (0.308 mL, 2.43 mmol, 1.1 equiv) was added to amixture of3-bromomethyl-8-(2,6-dichloro-3,5-dimethoxy-phenyl)-quinoxaline-5-carbonitrileand2-bromomethyl-8-(2,6-dichloro-3,5-dimethoxy-phenyl)-quinoxaline-5-carbonitrile(Step 82.3) (1 g, 2.21 mmol) and Cs₂CO₃ (3.52 g, 20 mmol, 1.5 equiv) inDMF (50 mL). The reaction mixture was stirred for 10 min at rt, quenchedby addition of a saturated aqueous solution of NaHCO₃ (150 mL) andextracted with EtOAc (2×300 mL). The organic phase was washed with asaturated aqueous solution of NaHCO₃ (150 mL), dried (Na₂SO₄), filteredand concentrated. The crude product was purified by silica gel columnchromatography (DCM/MeOH, 1:0→95:5) to afford 0.71 g of a mixture of8-(2,6-dichloro-3,5-dimethoxy-phenyl)-3-(4-ethyl-piperazin-1-ylmethyl)-quinoxaline-5-carbonitrileand8-(2,6-dichloro-3,5-dimethoxy-phenyl)-2-(4-ethyl-piperazin-1-ylmethyl)-quinoxaline-5-carbonitrile

Step 82.3:3-Bromomethyl-8-(2,6-dichloro-3,5-dimethoxy-Phenyl)-quinoxaline-5-carbonitrileand2-bromomethyl-8-(2,6-dichloro-3,5-dimethoxy-phenyl)-quinoxaline-5-carbonitrile

A mixture of8-(2,6-dichloro-3,5-dimethoxy-phenyl)-3-methyl-quinoxaline-5-carbonitrileand8-(2,6-dichloro-3,5-dimethoxy-phenyl)-2-methyl-quinoxaline-5-carbonitrile(Step 82.4) (4.93 g, 13.2 mmol) and NBS (3.52 g, 20 mmol, 1.5 equiv) inDMF (100 mL) was stirred at 80° C. for 3 h. Further NBS (2.35 g, 1equiv) was added and the reaction mixture was stirred at 100° for 2 h,allowed to cool to rt, quenched by addition of a saturated aqueoussolution of NaHCO₃ (250 mL) and extracted with EtOAc (2×300 mL). Theorganic phase was washed with a saturated aqueous solution of NaHCO₃(150 mL), dried (Na₂SO₄), filtered and concentrated. The crude productwas purified by silica gel column chromatography (Hex/EtOAc, 9:1→7:3) toafford 2.37 g of a mixture of3-bromomethyl-8-(2,6-dichloro-3,5-dimethoxy-phenyl)-quinoxaline-5-carbonitrileand2-bromomethyl-8-(2,6-dichloro-3,5-dimethoxy-phenyl)-quinoxaline-5-carbonitrile.

Step 82.4:8-(2,6-Dichloro-3,5-dimethoxy-phenyl)-3-methyl-quinoxaline-5-carbonitrileand8-(2,6-dichloro-3,5-dimethoxy-phenyl)-2-methyl-quinoxaline-5-carbonitrile

Sulfuryl chloride (2.14 mL, 26.6 mmol, 1.8 equiv) was added dropwise toa cold (5° C.) suspension of8-(3,5-dimethoxy-phenyl)-3-methyl-quinoxaline-5-carbonitrile and8-(3,5-dimethoxy-phenyl)-2-methyl-quinoxaline-5-carbonitrile (Step 82.5)(4.51 g, 14.8 mmol) in CH₃CN (80 mL). The reaction mixture was stirredat 5° C. for 10 min, quenched by addition of a saturated aqueoussolution of NaHCO₃ (250 mL) and extracted with EtOAc (2×300 mL). Theorganic phase was washed with a saturated aqueous solution of NaHCO₃(150 mL), dried (Na₂SO₄), filtered and concentrated. The crude productwas purified by silica gel column chromatography (Hex/EtOAc, 9:1→2:3) toafford 4.93 g of a mixture of8-(2,6-dichloro-3,5-dimethoxy-phenyl)-3-methyl-quinoxaline-5-carbonitrileand8-(2,6-dichloro-3,5-dimethoxy-phenyl)-2-methyl-quinoxaline-5-carbonitrile.

Step 82.5: 8-(3,5-Dimethoxy-phenyl)-3-methyl-quinoxaline-5-carbonitrileand 8-(3,5-dimethoxy-phenyl)-2-methyl-quinoxaline-5-carbonitrile

A mixture of 8-bromo-5-(3,5-dimethoxy-phenyl)-2-methyl-quinoxaline and5-bromo-8-(3,5-dimethoxy-phenyl)-2-methyl-quinoxaline (Step 82.6) (6.07g, 16.9 mmol) and CuCN (1.98 g, 22 mmol, 1.3 equiv) in NMP (50 mL) wasstirred for 5 h at 160° C., under an argon atmosphere. The reactionmixture was allowed to cool to rt, quenched by addition of a saturatedaqueous solution of NaHCO₃ (250 mL) and extracted with EtOAc. Theorganic phase was washed with a saturated aqueous solution of NaHCO₃(2×100 mL), dried (Na₂SO₄), filtered and concentrated. The crude productwas purified by silica gel column chromatography (Hex/EtOAc, 9:1→2:3) toafford 4.51 g of a mixture of8-(3,5-dimethoxy-phenyl)-3-methyl-quinoxaline-5-carbonitrile and8-(3,5-dimethoxy-phenyl)-2-methyl-quinoxaline-5-carbonitrile.

Step 82.6: 8-Bromo-5-(3,5-dimethoxy-phenyl)-2-methyl-quinoxaline and5-bromo-8-(3,5-dimethoxy-phenyl)-2-methyl-quinoxaline

A mixture of 3,5-dimethoxyphenylboronic acid (Step 1.8) (4 g, 22 mmol)in EtOH (125 mL) was added dropwise to a mixture of5,8-dibromo-2-methyl-quinoxaline (Step 82.7) (13.2 g, 43.8 mmol, 2equiv), PdCl₂(dPPf) (483 mg, 0.66 mmol, 0.03 equiv), Na₂CO₃ (2 Msolution in H₂O, 44 mL, 88 mmol, 4 equiv) in toluene (250 mL) at 105°C., under an argon atmosphere. The reaction mixture was stirred at 105°C. for 4.5 h, allowed to cool to rt, quenched by addition of a saturatedaqueous solution of NaHCO₃ and extracted with EtOAc. The organic phasewas washed with a saturated aqueous solution of NaHCO₃, dried (Na₂SO₄),filtered and concentrated. The crude product was purified by silica gelcolumn chromatography (Hex/EtOAc, 1:0→85:15) to afford 6.07 g of amixture of 8-bromo-5-(3,5-dimethoxy-phenyl)-2-methyl-quinoxaline and5-bromo-8-(3,5-dimethoxy-phenyl)-2-methyl-quinoxaline.

Step 82.7: 5,8-Dibromo-2-methyl-quinoxaline

A 40% aqueous solution of methylglyoxal (6.7 M, 6.3 mL, 112 mmol, 1.48equiv) was added to a suspension of 3,6-dibromo-benzene-1,2-diamine(Step 1.6) (20 g, 75.5 mmol) in EtOH (400 mL). The reaction mixture wasstirred for 2 h at rt and for 0.5 h at reflux, allowed to cool andfiltered to afford 7.66 g of the title compound. The filtrate wasconcentrated and the residue triturated in EtOAc and filtered. Thefiltrate was concentrated and the residue was purified by silica gelcolumn chromatography (Hex/EtOAc, 1:0→9:1) to provide additional 2.15 gof the title compound. The title compound: ESI-MS: 300.9/302.9/304.9[M+H]⁺; t_(R)=4.81 min (System 1); TLC: R_(f)=0.90 (Hex/EtOAc, 1:1).

Example 838-(2,6-Dichloro-3,5-dimethoxy-phenyl)-2-(4-ethyl-piperazin-1-ylmethyl)-quinoxaline-5-carboxylicacid pyridin-3-ylamide

The title compound was prepared in analogy to the procedure described inStep 14.1 but using 3-aminopyridine,8-(2,6-dichloro-3,5-dimethoxy-phenyl)-2-(4-ethyl-piperazin-1-ylmethyl)-quinoxaline-5-carboxylicacid (Step 83.1) and stirring the reaction mixture for 2 days at rt.Title compound: ESI-MS: 581.0/583.2 [M+H]⁺; t_(R)=3.04 min (System 1);TLC: R_(f)=0.33 (DCM/MeOH, 9:1).

Step 83.1:8-(2,6-Dichloro-3,5-dimethoxy-phenyl)-2-(4-ethyl-piperazin-1-ylmethyl)-quinoxaline-5-carboxylicacid

A solution of KOH (0.818 g, 14.6 mmol, 10 equiv) in H₂O (20 mL) wasadded to 710 mg (1.46 equiv) of the quinoxaline-5-carbonitriles mixture(Step 82.2) in ethylene glycol (20 mL). The reaction mixture was stirredat 150° C. for 3 h, allowed to cool to rt and washed with EtOAc (2×100mL). The aqueous layer was acidified to pH 3-4 by addition of 1 N HCl.The resulting suspension was filtered. The filtrate was extracted withDCM (2×100 mL). The organic layer was dried (Na₂SO₄), filtered andconcentrated. The residue was triturated in 1 N HCl (3 mL) and filtered.The filtrate was basified to pH 5 and extracted with DCM (2×100 mL). Theorganic layer was dried (Na₂SO₄), filtered and concentrated to afford121 mg of the title compound as a white solid: ES-MS: 505.0/506.6[M+H]⁺; t_(R)=3.45 min (System 1).

Example 848-(2,6-Dichloro-3,5-dimethoxy-phenyl)-2-(4-ethyl-piperazin-1-ylmethyl)-quinoxaline-5-carboxylicacid pyridin-2-ylamide

The title compound was prepared in analogy to the procedure described inStep 14.1 but using 2-aminopyridine,8-(2,6-dichloro-3,5-dimethoxy-phenyl)-2-(4-ethyl-piperazin-1-ylmethyl)-quinoxaline-5-carboxylicacid (Step 83.1) and stirring the reaction mixture for 2 days at rt.Title compound: ESI-MS: 581.0/583.2 [M+H]⁺; t_(R)=3.62 min (System 1);TLC: R_(f)=0.45 (DCM/MeOH, 9:1).

Example 858-(2,6-Dichloro-3,5-dimethoxy-phenyl)-2-[(2-dimethylamino-ethyl)-methyl-amino]-quinoxaline-5-carboxylicacid (1H-imidazol-2-yl)-amide

The title compound was prepared in analogy to the procedures describedin Example 14 but using8-(2,6-dichloro-3,5-dimethoxy-phenyl)-2-[(2-dimethylamino-ethyl)-methyl-amino]-quinoxaline-5-carboxylicacid (Step 85.1) in Step 14.1. Title compound: ESI-MS: 544.0/545.9[M+H]⁺; t_(R)=3.13 min (System 1); TLC: R_(f)=0.21 (DCM/MeOH/NH₃ ^(aq),91:8:1).

Step 85.1:8-(2,6-Dichloro-3,5-dimethoxy-Phenyl)-2-[(2-dimethylamino-ethyl)-methyl-amino]-quinoxaline-5-carboxylicacid

A solution of KOH (268 mg, 4.79 mmol, 10 equiv) in H₂O (2 mL) was addedto8-(2,6-dichloro-3,5-dimethoxy-phenyl)-2-[(2-dimethylamino-ethyl)-methyl-amino]-quinoxaline-5-carbonitrile(Step 85.2) (220 mg, 0.48 mmol) in ethylene glycol (2 mL). The reactionmixture was stirred at 150° C. for 48 h, allowed to cool to rt, dilutedwith Et₂O/H₂O, and extracted with Et₂O. The aqueous phase was acidifiedto pH 5 by addition of 6 N HCl. Vacuum filtration of the resultingsuspension afforded 450 mg of the title compound as an impure yellowsolid, which was used without further purification: ESI-MS: 479.0/480.9[M+H]⁺; t_(R)=3.75 min (System 1).

Step 85.2:8-(2,6-Dichloro-3,5-dimethoxy-Phenyl)-2-[(2-dimethylamino-ethyl)-methyl-amino]-quinoxaline-5-carbonitrile

A mixture of8-(2,6-dichloro-3,5-dimethoxy-phenyl)-2-[(2-dimethylamino-ethyl)-methyl-amino]-quinoxaline-5-carbonitrile(Step 85.3) (210 mg, 0.53 mmol) and N,N,N′-triethylethylene diamine(0.14 mL, 1.07 mmol, 2 equiv) in NMP (2 mL) was stirred at 120° C. for 5min, allowed to cool, diluted with EtOAc/H₂O and extracted with EtOAc.The organic phase was washed with H₂O and brine, dried (Na₂SO₄),filtered and concentrated. The residue was triturated in Et₂O to provide225 mg of the title compound as a yellow solid: ESI-MS: 460.1/461.9[M+H]⁺; t_(R)=3.97 min (System 1).

Step 85.3:2-Chloro-8-(2,6-dichloro-3,5-dimethoxy-phenyl)-quinoxaline-5-carbonitrile

Sulfuryl chloride (0.08 mL, 0.98 mmol, 2 equiv) was added dropwise to acold (5° C.) suspension of2-chloro-8-(3,5-dimethoxy-phenyl)-quinoxaline-5-carbonitrile (Step 85.4)(160 mg, 0.49 mmol) in CH₃CN (3 mL). The reaction mixture was stirred at5° C. for 10 min, quenched by addition of H₂O, and concentrated. Theresidue was taken up in DCM, washed with a saturated aqueous solution ofNaHCO₃, H₂O and brine, dried (Na₂SO₄), filtered and concentrated.Trituration of the residue in Et₂O provided 163 mg of the title compoundas a white solid: ESI-MS: 394.0/395.6/396.3 [M+H]⁺; t_(R)=5.13 min(System 1).

Step 85.4: 2-Chloro-8-(3,5-dimethoxy-phenyl)-quinoxaline-5-carbonitrile

A mixture of8-(3,5-dimethoxy-phenyl)-2-hydroxy-quinoxaline-5-carbonitrile (Step85.5) (100 mg, 0.33 mmol) and POCl₃ (1 mL) was stirred at 120° C. for 3h, allowed to cool to rt and concentrated. The residue was diluted withDCM/NaHCO₃ saturated aqueous solution and extracted with DCM. Theorganic phase was washed with H₂O and brine, dried (Na₂SO₄), filteredand concentrated. The crude product was purified by silica gel columnchromatography (Hex/EtOAc, 7:3) to afford 90 mg of the title compound asa yellow solid: ES-MS: 326.1 [M+H]⁺; t_(R)=5.02 min (System 1);R_(f)=0.34 (Hex/EtOAc, 7:3).

Step 85.5: 8-(3,5-Dimethoxy-phenyl)-2-hydroxy-quinoxaline-5-carbonitrile

A mixture of 5-bromo-8-(3,5-dimethoxy-phenyl)-quinoxalin-2-ol and8-bromo-5-(3,5-dimethoxy-phenyl)-quinoxalin-2-ol (Step 85.6) (609 mg,1.7 mmol) (Step 1.4) and CuCN (183 mg, 2.0 mmol, 1.2 equiv) in NMP (5mL) was stirred at 180° C. for 2 h. The reaction mixture was allowed tocool to rt, diluted with EtOAc/10% aqueous solution of ethylenediamine(25 mL) and extracted with EtOAc. The aqueous phase was acidified to pH5 and extracted with EtOAc. The combined organic extracts were washedwith H₂O and brine, dried (Na₂SO₄), filtered and concentrated. Theresidue was purified by silica gel column chromatography (Hex/EtOAc,7:3) to afford 103 mg of the title compound as a yellow solid: ES-MS:308.1 [M+H]⁺; t_(R)=4.05 min (System 1); R_(f)=0.35 (Hex/EtOAc, 7:3).

Step 85.6: 5-Bromo-8-(3,5-dimethoxy-phenyl)-quinoxalin-2-ol and8-bromo-5-(3,5-dimethoxy-phenyl)-quinoxalin-2-ol

A mixture of 4-bromo-3′,5′-dimethoxy-biphenyl-2,3-diamine (Step 85.7) (1g, 3.1 mmol) and glyoxylite acid monohydrate (313 mg, 3.4 mmol, 1.1equiv) in EtOH (20 mL) was stirred at reflux for 15 min, allowed to coolto rt. The resulting yellow solid was collected by vacuum filtration toprovide 397 mg of the title mixture. The filtrate was concentrated andthe residue was purified silica gel column chromatography (Hex/EtOAc,1:1) to afford additional 225 mg of the title mixture.

Step 85.7: 4-Bromo-3′,5′-dimethoxy-biphenyl-2,3-diamine

A mixture of 3,5-dimethoxyphenylboronic acid (15.1 g, 82.7 mmol, 1.1equiv) (Step 1.8) in EtOH (50 mL) was added dropwise to a mixture of3,6-dibromo-benzene-1,2-diamine (20 g, 75.2 mmol) (Step 1.6),PdCl₂(dPPf) (6.1 g, 7.5 mmol, 0.1 equiv), Na₂CO₃ (2 M solution in H₂O,150 mL, 300.8 mmol, 4 equiv) in toluene (300 mL) at 105° C., under anargon atmosphere. The reaction mixture was stirred at 105° C. for 3 h,allowed to cool to rt, diluted with EtOAc and H₂O and extracted withEtOAc. The organic phase was washed with H₂O and brine, dried (Na₂SO₄),filtered and concentrated. The crude product was purified by silica gelcolumn chromatography (DCM) followed by trituration in EtOH to afford9.2 g of the title compound as a white solid: ES-MS: 323.0/325.0 [M+H]⁺;t_(R)=4.43 min (System 1); R_(f)=0.15 (DCM).

Example 868-(2,6-Dichloro-3,5-dimethoxy-phenyl)-2-[(2-dimethylamino-ethyl)-methyl-amino]-quinoxaline-5-carboxylicacid pyridin-2-ylamide

The title compound was prepared in analogy to the procedure described inStep 14.1 but using8-(2,6-dichloro-3,5-dimethoxy-phenyl)-2-[(2-dimethylamino-ethyl)-methyl-amino]-quinoxaline-5-carboxylicacid (Step 85.1) and 2-aminopyridine. Title compound: ESI-MS:555.0/557.2 [M+H]⁺; t_(R)=3.61 min (System 1); TLC: R_(f)=0.42(DCM/MeOH/NH₃ ^(aq), 94:5:1).

Example 878-(2,6-Dichloro-3,5-dimethoxy-phenyl)-2-[(2-dimethylamino-ethyl)-methyl-amino]-quinoxaline-5-carboxylicacid pyridin-3-ylamide

The title compound was prepared in analogy to the procedure described inStep 14.1 but using8-(2,6-dichloro-3,5-dimethoxy-phenyl)-2-[(2-dimethylamino-ethyl)-methyl-amino]-quinoxaline-5-carboxylicacid (Step 85.1) and 3-aminopyridine. Title compound: ESI-MS:555.0/557.2 [M+H]⁺; t_(R)=3.16 min (System 1); TLC: R_(f)=0.20(DCM/MeOH/NH₃ ^(aq), 94:5:1).

Example 888-(2,6-Difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid[6-(4-ethyl-piperazin-1-ylmethyl)-pyridin-3-yl]-amide

The title compound was prepared in analogy to the procedure described inStep 14.1 but using8-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid(Step 88.1), 6-(4-ethyl-piperazin-1-ylmethyl)-pyridin-3-ylamine(prepared as described in Example 39 but using N-ethyl-piperazine inStep 39.2), and stirring the reaction mixture for 3 h at rt. The crudeproduct was purified by silica gel column chromatography (DCM/MeOH/NH₃^(aq), 94:5:1). Title compound: ESI-MS: 549.1 [M+H]⁺; t_(R)=3.22 min(System 1); TLC: R_(f)=0.13 (DCM/MeOH/NH₃ ^(aq), 94:5:1).

Step 88.1:8-(2,6-Difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid

A solution of KOH (2.4 g, 42.8 mmol, 10 equiv) in H₂O (10 mL) was addedto 8-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carbonitrile(Step 88.2) (1.4 g mg, 4.3 mmol) in ethylene glycol (20 mL). Thereaction mixture was stirred at 150° C. for 4 h, allowed to cool to rt,diluted with Et₂O/H₂O, and extracted with Et₂O. The aqueous phase wasacidified to pH 5 by addition of 6 N HCl. Vacuum filtration of theresulting suspension afforded 1.47 g of the title compound as a brownsolid, which was used without further purification: ESI-MS: 347.1[M+H]⁺; t_(R)=4.22 min (System 1).

Step 88.2:8-(2,6-Difluoro-3,5-dimethoxy-Phenyl)-quinoxaline-5-carbonitrile

A mixture of 5-bromo-8-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoxaline(Step 88.3) (1.1 g, 2.9 mmol) (Step 88.3) and CuCN (312 mg, 3.4 mmol,1.2 equiv) in NMP (10 mL) was stirred for 4 h at 150° C., under an argonatmosphere. The reaction mixture was allowed to cool to rt, diluted withDCM/(10% aqueous solution of ethylenediamine) (100 mL) and extractedwith DCM. The organic phase was washed with H₂O and brine, dried(Na₂SO₄), filtered and concentrated. The residue was triturated in EtOActo provide 702 mg of the title compound as a beige solid: ESI-MS: 328.1[M+H]⁺; t_(R)=4.48 min (System 1).

Step 88.3: 5-Bromo-8-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoxaline

SelectFluor (20.5 g, 58 mmol, 2 equiv) was added portionwise to asolution of 5-bromo-8-(3,5-dimethoxy-phenyl)-quinoxaline (Step 1.4) (10g, 29 mmol) in CH₃CN (300 mL) at rt. The reaction mixture was stirred atrt for 0.5 h, quenched by addition of H₂O and concentrated to removeCH₃CN. The resulting mixture was diluted with EtOAc/H₂O and filtered toprovide a white solid (batch 1). The filtrate was extracted with EtOAc.The organic phase was washed with H₂O and brine, dried (Na₂SO₄),filtered and concentrated to afford batch 2. The two batches werecombined and purified by silica gel MPLC (Hex/EtOAc, 7:3) to afford asample of 5-bromo-8-(2-fluoro-3,5-dimethoxy-phenyl)-quinoxaline (Step94.3) and a sample of the title compound which was further purified bytrituration in EtOAc to provide 2.28 g of a white solid. Title compound:ESI-MS: 381.0/382.9 [M+H]⁺; t_(R)=4.92 min (System 1); TLC: R_(f)=0.26(Hex/EtOAc, 7:3).

Example 898-(2,6-Difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid[6-(4-methyl-piperazin-1-ylmethyl)-pyridin-3-yl]-amide

The title compound was prepared in analogy to the procedure described inStep 14.1 but using8-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid(Step 88.1), 6-(4-methyl-piperazin-1-ylmethyl)-pyridin-3-ylamine (Step39.1), and stirring the reaction mixture for 16 h at rt. The crudeproduct was purified by silica gel column chromatography (DCM/MeOH/NH₃^(aq), 94:5:1) followed by trituration in Et₂O. Title compound: ESI-MS:535.1 [M+H]⁺; t_(R)=3.15 min (System 1); TLC: R_(f)=0.13 (DCM/MeOH/NH₃^(aq), 94:5:1).

Example 908-(2,6-Difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acidpyridin-3-ylamide

The title compound was prepared in analogy to the procedure described inStep 14.1 but using8-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid(Step 88.1), 3-aminopyridine, and stirring the reaction mixture for 72 hat rt. The crude product was purified by silica gel columnchromatography (DCM/MeOH/NH₃ ^(aq), 96:3:1) followed by trituration inEt₂O. Title compound: ESI-MS: 423.1 [M+H]⁺; t_(R)=3.53 min (System 1);TLC: R_(f)=0.56 (DCM/MeOH/NH₃ ^(aq), 96:3:1).

Example 918-(2,6-Difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acidpyridin-2-ylamide

The title compound was prepared in analogy to the procedure described inStep 14.1 but using8-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid(Step 88.1), 2-aminopyridine, and stirring the reaction mixture for 72 hat rt. The crude product was purified by silica gel columnchromatography (DCM/MeOH/NH₃ ^(aq), 96:3:1), followed by trituration inEt₂O, a second silica gel column chromatography (Hex/EtOAc, 1:4) and anadditional trituration in Et₂O. Title compound: ESI-MS: 423.1 [M+H]⁺;t_(R)=4.21 min (System 1); TLC: R_(f)=0.19 (Hex/EtOAc, 1:4).

Example 928-(2,6-Difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid[5-(4-ethyl-piperazin-1-ylmethyl)-pyridin-2-yl]-amide

The title compound was prepared in analogy to the procedure described inStep 14.1 but using8-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid(Step 88.1), 5-(4-ethyl-piperazin-1-ylmethyl)-pyridin-2-ylamine (Step26.1), and stirring the reaction mixture for 48 h at rt and for 5 h at50° C. after addition of further 1.2 equiv of TBTU. The crude productwas purified by silica gel column chromatography (DCM/MeOH/NH₃ ^(aq),94:5:1). Title compound: ESI-MS: 549.1 [M+H]⁺; t_(R)=3.39 min (System1); TLC: R_(f)=0.24 (DCM/MeOH/NH₃ ^(aq), 94:5:1).

Example 938-(2,6-Difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid(4-pyrrolidin-1-ylmethyl-1H-imidazol-2-yl)-amide

The title compound was prepared in analogy to the procedures describedin Example 14 but stirring the reaction mixture for 6 h at 65° C. andusing 8-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylicacid (Step 88.1). 2-Nitro-4-pyrrolidin-1-ylmethyl-1H-imidazole (Step19.1) instead of 2-nitroimidazole was used in Step 14.3, and Raneynickel and MeOH/THF (1:1) instead of palladium on carbon and MeOH inStep 14.2. The title compound: ESI-MS: 495.0 [M+H]⁺; t_(R)=3.28 min(System 1); TLC: R_(f)=0.08 (DCM/MeOH/NH₃ ^(aq), 94:5:1).

Example 94 8-(2-Fluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylicacid(5-{[(2-dimethylamino-ethyl)-methyl-amino]-methyl}-pyridin-2-yl)-amide

The title compound was prepared in analogy to the procedure described inStep 14.1 but using8-(2-fluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid (Step94.1),N-(6-amino-pyridin-3-ylmethyl)-N,N′,N′-trimethyl-ethane-1,2-diamine(prepared as described in Example 26 but usingN,N,N′-trimethyl-ethane-1,2-diamine in Step 26.2) and stirring thereaction mixture for 18 h at rt. The crude product was purified bysilica gel column chromatography (DCM/MeOH/NH₃ ^(aq), 94:5:1). Titlecompound: ESI-MS: 519.2 [M+H]⁺; t_(R)=3.26 min (System 1); TLC:R_(f)=0.13 (DCM/MeOH/NH₃ ^(aq), 94:5:1).

Step 94.1: 8-(2-Fluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylicacid

A solution of KOH (2.95 g, 52.7 mmol, 10 equiv) in H₂O (20 mL) was addedto 8-(2-fluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carbonitrile (Step94.2) (1.63 g mg, 5.3 mmol) in ethylene glycol (20 mL). The reactionmixture was stirred at 150° C. for 5 h, allowed to cool to rt, dilutedwith Et₂O/H₂O, and extracted with Et₂O. The aqueous phase was acidifiedto pH 3 by addition of HCl. The resulting yellow solid was collected byvacuum filtration to provide 1.71 g of the title compound: ESI-MS: 329.1[M+H]⁺; t_(R)=4.18 min (System 1).

Step 94.2: 8-(2-Fluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carbonitrile

A mixture of 5-bromo-8-(2-fluoro-3,5-dimethoxy-phenyl)-quinoxaline (Step94.3) (3.09 g, 8.5 mmol) and CuCN (918 mg, 10.2 mmol, 1.2 equiv) in NMP(30 mL) was stirred for 6.5 h at 160° C., under an argon atmosphere. Thereaction mixture was allowed to cool to rt, diluted with DCM/(10%aqueous solution of ethylenediamine) (200 mL, v/v 1:1), filtered throughcelite and the filtrate extracted with DCM. The organic phase was washedwith H₂O and brine, dried (Na₂SO₄), filtered and concentrated. Theresidue was triturated in DCM to provide 1.63 g of the title compound asa white solid: ESI-MS: 310.1 [M+H]⁺; t_(R)=4.41 min (System 1).

Step 94.3: 5-Bromo-8-(2-fluoro-3,5-dimethoxy-phenyl)-quinoxaline

SelectFluor (20.5 g, 58 mmol, 2 equiv) was added portionwise to asolution of 5-bromo-8-(3,5-dimethoxy-phenyl)-quinoxaline (Step 1.4) (10g, 29 mmol) in CH₃CN (300 mL) at rt. The reaction mixture was stirred atrt for 0.5 h, quenched by addition of H₂O and concentrated to removeCH₃CN. The resulting mixture was diluted with EtOAc/H₂O and filtered toprovide a white solid (batch 1). The filtrate was extracted with EtOAc.The organic phase was washed with H₂O and brine, dried (Na₂SO₄),filtered and concentrated to afford batch 2. The two batches werecombined and purified by silica gel MPLC (Hex/EtOAc, 7:3) to afford asample of 5-bromo-8-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoxaline(Step 88.3) and a sample of the title compound which was furtherpurified by trituration in EtOAc to provide 2.42 g of a white solid.Title compound: ESI-MS: 364.9 [M+H]⁺; t_(R)=4.95 min (System 1); TLC:R_(f)=0.34 (Hex/EtOAc, 7:3).

Example 95 8-(2-Fluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylicacid [5-(4-ethyl-piperazin-1-ylmethyl)-pyridin-2-yl]-amide

The title compound was prepared in analogy to the procedure described inStep 14.1 but using8-(2-fluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid (Step94.1), 5-(4-ethyl-piperazin-1-ylmethyl)-pyridin-2-ylamine hydrochloride(Step 26.1) and stirring the reaction mixture for 6 days at rt. Thecrude product was purified by silica gel column chromatography(DCM/MeOH/NH₃ ^(aq), 94:5:1). Title compound: ESI-MS: 531.2 [M+H]⁺;t_(R)=3.40 min (System 1); TLC: R_(f)=0.19 (DCM/MeOH/NH₃ ^(aq), 94:5:1).

Example 96 8-(2-Fluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylicacid (4-pyrrolidin-1-ylmethyl-1H-imidazol-2-yl)-amide

The title compound was prepared in analogy to the procedures describedin Example 14 but stirring the reaction mixture for 6 h at 65° C. andusing 8-(2-fluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid(Step 94.1). 2-Nitro-4-pyrrolidin-1-ylmethyl-1H-imidazole (Step 19.1)instead of 2-nitroimidazole was used in Step 14.3, and Raney nickel andMeOH/THF (1:1) instead of palladium on carbon and MeOH in Step 14.2. Thetitle compound: ESI-MS: 477.2 [M+H]⁺; t_(R)=3.28 min (System 1); TLC:R_(f)=0.11 (DCM/MeOH/NH₃ ^(aq), 94:5:1).

Example 97 8-(3-Methoxy-2,5-dimethyl-phenyl)-quinoxaline-5-carboxylicacid [5-(4-ethyl-piperazin-1-ylmethyl)-pyridin-2-yl]-amide

The title compound was prepared in analogy to the procedure described inStep 14.1 but using8-(3-methoxy-2,5-dimethyl-phenyl)-quinoxaline-5-carboxylic acid (Step97.1), 5-(4-ethyl-piperazin-1-ylmethyl)-pyridin-2-ylamine hydrochloride(Step 26.1) and stirring the reaction mixture for 24 h at rt. The crudeproduct was purified by silica gel column chromatography (DCM/MeOH/NH₃^(aq), 94:5:1). Title compound: ESI-MS: 511.1 [M+H]⁺; t_(R)=3.75 min(System 1); TLC: R_(f)=0.29 (DCM/MeOH/NH₃ ^(aq), 94:5:1).

Step 97.1: 8-(3-Methoxy-2,5-dimethyl-phenyl)-quinoxaline-5-carboxylicacid

The title compound was prepared in analogy to the procedures describedin Steps 1.2-1.4 but with the following modifications. In Step 1.2, thereaction mixture was stirred at 150° C. for 4 h. In Step 1.3, thereaction mixture was stirred at 160° C. for 5 h; DCM was used instead ofEtOAc; the crude product was purified by silica gel columnchromatography (Hex/EtOAC, 1:1). 3-Methoxy-2,5-dimethyl-phenyl boronicacid (Step 97.2) was used in Step 1.4. Title compound: ESI-MS: 309.2[M+H]⁺; t_(R)=4.71 min (System 1).

Step 97.2: 3-Methoxy-2,5-dimethyl-phenyl boronic acid

The title compound was prepared in analogy to the procedure described inStep 1.8 but using 1-bromo-3-methoxy-2,5-dimethyl-benzene (Journal ofOrganic Chemistry 1992, 57(10), 2774-83). The title compound wasobtained as an impure sample and used without further purification.

Example 988-(2-Chloro-5-methoxy-3,6-dimethyl-phenyl)-quinoxaline-5-carboxylic acid[5-(4-ethyl-piperazin-1-ylmethyl)-pyridin-2-yl]-amide

The title compound was prepared in analogy to the procedure described inStep 14.1 but using8-(2-chloro-5-methoxy-3,6-dimethyl-phenyl)-quinoxaline-5-carboxylic acid(Step 98.1), 5-(4-ethyl-piperazin-1-ylmethyl)-pyridin-2-ylaminehydrochloride (Step 26.1) and stirring the reaction mixture for 20 h atrt. The crude product was purified by silica gel column chromatography(DCM/MeOH/NH₃ ^(aq), 94:5:1). Title compound: ESI-MS: 545.0 [M+H]⁺;t_(R)=3.91 min (System 1); TLC: R_(f)=0.23 (DCM/MeOH/NH₃ ^(aq), 94:5:1).

Step 98.1:8-(2-Chloro-5-methoxy-3,6-dimethyl-phenyl)-quinoxaline-5-carboxylic acid

Sulfuryl chloride (29 μL, 0.37 mmol) in CH₃CN (1 mL) was added dropwiseto a cold (−5° C.) suspension of8-(3-methoxy-2,5-dimethyl-phenyl)-quinoxaline-5-carboxylic acid (Step97.1) (113 mg, 0.37 mmol) in CH₃CN (4 mL). The reaction mixture wasstirred for 10 min at −5° C., quenched by addition of H₂O (1 mL) andfiltered to afford 42 mg of the title compound as a yellow solid. Titlecompound: ESI-MS: 343.0 [M+H]⁺; t_(R)=4.90 min (System 1).

Example 99 8-(2,5-Dimethyl-1-oxy-pyridin-3-yl)-quinoxaline-5-carboxylicacid [5-(4-ethyl-piperazin-1-ylmethyl)-pyridin-2-yl]-amide

The title compound was prepared in analogy to the procedure described inStep 14.1 but using8-(2,5-dimethyl-1-oxy-pyridin-3-yl)quinoxaline-5-carboxylic acid (Step99.1), 5-(4-ethyl-piperazin-1-ylmethyl)-pyridin-2-ylamine hydrochloride(Step 26.1) and stirring the reaction mixture for 24 h at rt. The crudeproduct was purified by silica gel column chromatography (DCM/MeOH/NH₃^(aq), 91.5:7.5:1), followed by trituration in Et₂O. Title compound:ESI-MS: 498.2 [M+H]⁺; t_(R)=2.41 min (System 1); TLC: R_(f)=0.09(DCM/MeOH/NH₃ ^(aq), 91.5:7.5:1).

Step 99.1: 8-(2,5-Dimethyl-1-oxy-pyridin-3-yl)-quinoxaline-5-carboxylicacid

The title compound was prepared in analogy to the procedures describedin Steps 1.2-1.3 but with the following modifications. In Step 1.2,8-(2,5-dimethyl-1-oxy-pyridin-3-yl)-quinoxaline-5-carbonitrile (Step99.2) was used; the reaction mixture was stirred at 150° C. for 1 h; theaqueous phase was acidified to pH 1 by addition of 6 N HCl and extractedwith DCM; the organic phase was concentrated to afford the titlecompound. Title compound: ESI-MS: 296.1 [M+H]⁺; t_(R)=2.51 min (System1).

Step 99.2:8-(2,5-Dimethyl-1-oxy-pyridin-3-yl)-quinoxaline-5-carbonitrile

mCPBA (55% in H₂O, 215 mg, 0.68 mmol, 1.2 equiv) was added to a cold (5°C.) solution of 8-(2,5-dimethyl-pyridin-3-yl)-quinoxaline-5-carbonitrile(Step 99.3) (148 mg, 0.57 mmol) in DCM (3 mL). The reaction mixture wasstirred at 5° C. for 20 min, diluted with DCM/saturated solution ofNaHCO₃ and extracted with DCM. The organic phase was washed with H₂O andbrine, dried (Na₂SO₄), filtered and concentrated to afford 106 mg of thetitle compound as a white solid. Title compound: ESI-MS: 277.2 [M+H]⁺;t_(R)=2.84 min (System 1).

Step 99.3: 8-(2,5-Dimethyl-pyridin-3-yl)-quinoxaline-5-carbonitrile

A mixture of 5-bromo-8-(2,5-dimethyl-pyridin-3-yl)-quinoxaline (Step99.4) (189 mg, 0.60 mmol) and CuCN (70 mg, 0.78 mmol, 1.3 equiv) in NMP(2 mL) was stirred for 6 h at 160° C., under an argon atmosphere. Thereaction mixture was allowed to cool to rt, diluted with DCM/10% aqueoussolution of ethylenediamine (25 mL), extracted with DCM. The organicphase was washed with H₂O and brine, dried (Na₂SO₄), filtered andconcentrated. The residue was purified by silica gel columnchromatography (DCM/MeOH/NH₃ ^(aq), 94:5:1) to afford 150 mg of thetitle compound as a yellow solid. Title compound: ESI-MS: 261.2 [M+H]⁺;t_(R)=1.92 min (System 1); TLC: R_(f)=0.68 (DCM/MeOH/NH₃ ^(aq), 94:5:1).

Step 99.4: 5-Bromo-8-(2,5-dimethyl-pyridin-3-yl)-quinoxaline

n-BuLi (1.6 M in hexanes, 6.7 mL, 10.8 mmol, 2.0 equiv) was addeddropwise to a cold (−78° C.) solution of 3-bromo-2,5-dimethyl-pyridine(Bulletin de la Societe Chimique de France, 1972, (6), 2466-81) (1 g,5.38 mmol) in Et₂O (20 mL), under an argon atmosphere. The reactionmixture was stirred for 1 h at −78° C. Triisopropyl borate (3.7 mL, 16.1mmol, 3.0 equiv) was then added. The reaction mixture was allowed towarm to rt, quenched by addition of a saturated solution of NH₄Cl (1mL), and concentrated. The residue was diluted with EtOAc/H₂O and the pHadjusted to 7. The aqueous layer was separated and extracted with EtOAc.The organic phase was dried (Na₂SO₄), filtered and concentrated toafford 170 mg of the title compound as a beige solid (batch 1). Theaqueous layer was concentrated, the residue combined with batch 1 anddissolved in EtOH (5 mL). This solution was added to a mixture of5,8-dibromo-quinoxaline (800 mg, 2.8 mmol) (Step 1.5), PdCl₂(dPPf) (113mg, 0.1 mmol, 0.05 equiv), Na₂CO₃ (2 M solution in H₂O, 5.6 mL, 11.1mmol, 4 equiv) in toluene (30 mL) at 105° C., under an argon atmosphere.The reaction mixture was stirred at 105° C. for 4 h, allowed to cool tort, diluted with EtOAc and H₂O, and extracted with EtOAc. The organicphase was washed with H₂O and brine, dried (Na₂SO₄), filtered andconcentrated in vacuo. The crude product was purified by silica gelcolumn chromatography (Hex/EtOAc, 1:4) to afford 250 mg of the titlecompound as a purple solid: ES-MS: 314.0/316.0 [M+H]⁺; t_(R)=2.63 min(System 1); R_(f)=0.09 (Hex/EtOAc, 1:4).

Example 1008-(2,6-Dichloro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid[5-((R)-3-hydroxy-pyrrolidin-1-ylmethyl)-pyridin-2-yl]-amide

The title compound was prepared in analogy to the procedure described inStep 14.1 but using (R)-1-(6-amino-pyridin-3-ylmethyl)-pyrrolidin-3-ol(Step 100.1) and stirring the reaction mixture for 72 h at rt. The crudeproduct was purified by silica gel column chromatography (DCM/NH₃ ^(aq),99:1→DCM/MeOH/NH₃ ^(aq), 96:3:1). Title compound: ESI-MS: 554.0/556.2[M+H]⁺; t_(R)=3.77 min (System 1); TLC: R_(f)=0.29 (DCM/MeOH, 9:1).

Step 100.1: (R)-1-(6-Amino-pyridin-3-ylmethyl)-pyrrolidin-3-ol

A mixture of[5-((R)-3-hydroxy-pyrrolidin-1-ylmethyl)-pyridin-2-yl]carbamic acidtert-butyl ester (Step 100.2) (210 mg, 0.72 mmol), a 4 N solution of HClin dioxane (2 mL), and MeOH (2 mL) was stirred for 16 h at rt andconcentrated. The residue was purified by silica gel columnchromatography (DCM/MeOH/NH₃ ^(aq), 89:10:1) to afford 125 mg of thetitle compound as a yellow oil. Title compound: ESI-MS: 194.1 [M+H]⁺;TLC: R_(f)=0.05 (DCM/MeOH, 9:1).

Step 100.2:[5-((R)-3-Hydroxy-pyrrolidin-1-ylmethyl)-pyridin-2-yl]-carbamic acidtert-butyl ester

A mixture of (5-methyl-pyridin-2-yl)-carbamic acid tert-butyl ester(Step 100.3) (10.7 g, 51.4 mmol), NBS (10.1 g, 56.7 mmol, 1.1 equiv),AIBN (843 mg, 5.14 mmol, 0.1 equiv) in CCl₄ (500 mL) was stirred for 1 hat relfux. NBS (1.8 g, 10.1 mmol, 0.2 equiv) was added and the mixturewas stirred at reflux for additional 30 min. The reaction mixture wasfiltered hot and the filtrate was concentrated. Trituration of theresidue in CH₃CN afforded of 12.88 g of impure(5-bromomethyl-pyridin-2-yl)-carbamic acid tert-butyl ester(intermediate 100.2). (R)-3-Hydroxypyrrolidine (181 mg, 2.1 mmol, 1.2equiv) was added to a mixture of intermediate 100.2 (500 mg, 1.75 mmol)and Cs₂CO₃ (684 mg, 2.1 mmol, 1.2 equiv) in DMF (5 ml). The reactionmixture was stirred for 24 h at rt, quenched by addition of a saturatedaqueous solution of NaHCO₃ (150 mL) and extracted with EtOAc. Theorganic layer was washed with a saturated aqueous solution of NaHCO₃,dried (Na₂SO₄), filtered and concentrated. The residue was purified bysilica gel column chromatography (DCM/NH₃ ^(aq), 99:1→DCM/MeOH/NH₃^(aq), 96:3:1) to afford 212 mg of the title compound as a white solid.Title compound: ESI-MS: 294.3 [M+H]⁺; t_(R)=1.95 min (System 1); TLC:R_(f)=0.14 (DCM/MeOH, 9:1).

Step 100.3: (5-Methyl-pyridin-2-yl)-carbamic acid tert-butyl ester

A solution of di-tert-butyl dicarbonate (33.3 g, 153 mmol, 1.1 equiv) inDCM (50 mL) was added dropwise to a solution of 2-amino-5-methylpyridine(15 g, 139 mmol) and DMAP (1.7 g, 13.9 mmol, 0.1 equiv) in DCM (50 mL)at rt, under an argon atmosphere. The reaction mixture was stirred for16 h at rt, quenched by addition of a saturated aqueous solution ofNaHCO₃ (100 mL) and extracted with DCM. The organic phase was washedwith a saturated aqueous solution of NaHCO₃, dried (Na₂SO₄), filteredand concentrated. The residue was purified by silica gel columnchromatography (Hex/EtOAc, 9:1) to afford 11.73 g of the title compoundas a white solid. Title compound: ESI-MS: 209.2 [M+H]⁺; t_(R)=2.40 min(System 1); TLC: R_(f)=0.86 (Hex/EtOAc, 1:1).

Example 1018-(2,6-Dichloro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid[5-((S)-3-hydroxy-pyrrolidin-1-ylmethyl)-pyridin-2-yl]-amide

The title compound was prepared in analogy to the procedure described inStep 14.1 but using (S)-1-(6-amino-pyridin-3-ylmethyl)-pyrrolidin-3-ol(Step 101.1) and stirring the reaction mixture for 20 h at rt. The crudeproduct was purified by silica gel column chromatography (DCM/NH₃ ^(aq),99:1→DCM/MeOH/NH₃ ^(aq), 96:3:1). Title compound: ESI-MS: 553.9/556.2[M+H]⁺; t_(R)=3.79 min (System 1); TLC: R_(f)=0.25 (DCM/MeOH, 9:1).

Step 101.1: (S)-1-(6-Amino-pyridin-3-ylmethyl)-pyrrolidin-3-ol

The title compound was prepared in analogy to the procedures describedin Steps 100.1-100.2 but using (S)-3-hydroxypyrrolidine in Step 100.2:194.2 [M+H]⁺; TLC: R_(f)=0.05 (DCM/MeOH, 9:1).

Example 1028-(2,6-Dichloro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid[5-(4-acetyl-piperazin-1-ylmethyl)-pyridin-2-yl]-amide

The title compound was prepared in analogy to the procedure described inStep 14.1 but using1-[4-(6-amino-pyridin-3-ylmethyl)-piperazin-1-yl]-ethanone (Step 102.1)and stirring the reaction mixture for 20 h at rt. The crude product waspurified by silica gel column chromatography (DCM/NH₃ ^(aq),99:1→DCM/MeOH/NH₃ ^(aq), 98:1:1). Title compound: ESI-MS: 595.0/597.2[M+H]⁺; t_(R)=3.82 min (System 1); TLC: R_(f)=0.42 (DCM/MeOH, 9:1).

Step 102.1: 1-[4-(6-Amino-pyridin-3-ylmethyl)-piperazin-1-yl]-ethanone

The title compound was prepared in analogy to the procedures describedin Steps 100.1-100.2 but using 1-acetylpiperazine in Step 100.2: 235.3[M+H]⁺; TLC: R_(f)=0.36 (DCM/MeOH, 9:1).

Example 1038-(2,6-Dichloro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid[5-(3-oxo-piperazin-1-ylmethyl)-pyridin-2-yl]-amide

The title compound was prepared in analogy to the procedure described inStep 14.1 but using 4-(6-amino-pyridin-3-ylmethyl)-piperazin-2-one (Step103.1) and stirring the reaction mixture for 72 h at rt. The crudeproduct was purified by silica gel column chromatography (DCM/MeOH/NH₃^(aq), 98:1:1) followed by trituration in Et₂O. Title compound: ESI-MS:567.0/568.7 [M+H]⁺; t_(R)=3.68 min (System 1); TLC: R_(f)=0.27(DCM/MeOH, 9:1).

Step 103.1: 4-(6-Amino-pyridin-3-ylmethyl)-piperazin-2-one

The title compound was prepared in analogy to the procedures describedin Steps 100.1-100.2 but using piperazin-2-one in Step 100.2: 207.2[M+H]⁺; TLC: R_(f)=0.14 (DCM/MeOH, 9:1).

Example 1048-(2,6-Dichloro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid[5-(1,1-dioxothiomorpholin-4-ylmethyl)-pyridin-2-yl]-amide

The title compound was prepared in analogy to the procedure described inStep 14.1 but using5-(1,1-dioxothiomorpholin-4-ylmethyl)-pyridin-2-ylamine (Step 104.1) andstirring the reaction mixture for 72 h at rt. The crude product waspurified by silica gel column chromatography (DCM/NH₃ ^(aq),99:1→DCM/MeOH/NH₃ ^(aq), 95:4:1) followed by trituration in Et₂O. Titlecompound: ESI-MS: 602.0 [M+H]⁺; t_(R)=4.01 min (System 1); TLC:R_(f)=0.38 (DCM/MeOH, 9:1).

Step 104.1: 5-(1,1-Dioxothiomorpholin-4-ylmethyl)-pyridin-2-ylamine

The title compound was prepared in analogy to the procedures describedin Steps 100.1-100.2 but using thiomorpholine-1,1-dioxide in Step 100.2:242.2 [M+H]⁺; TLC: R_(f)=0.33 (DCM/MeOH, 9:1).

Example 1058-(2,6-Dichloro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid(5-piperazin-1-ylmethyl-pyridin-2-yl)-amide

Intermediate 105 was prepared in analogy to the procedure described inStep 14.1 but using5-[4-(4-methoxy-benzyl)-piperazin-1-ylmethyl]-pyridin-2-ylamine (Step105.1) and stirring the reaction mixture for 72 h at rt: ESI-MS: 673.0[M+H]⁺; TLC: R_(f)=0.51 (DCM/MeOH, 9:1).

A mixture of intermediate 105 (200 mg, 0.3 mmol) and TFA (5 mL) wasstirred for 2 h at 120° C. in a microwave apparatus. The reactionmixture was neutralized by addition of NaHCO₃, extracted with EtOAc. Theorganic layer was washed with brine, dried (Na₂SO₄), filtered andconcentrated. The residue was purified by silica gel columnchromatography (DCM/NH₃ ^(aq), 99:1→DCM/MeOH/NH₃ ^(aq), 95:4:1) followedby trituration in Et₂O to afford 100 mg of the title compound as ayellow solid. Title compound: ESI-MS: 552.9/555.2 [M+H]⁺; t_(R)=3.42 min(System 1); TLC: R_(f)=0.09 (DCM/MeOH, 9:1).

Step 105.1:5-[4-(4-Methoxy-benzyl)-piperazin-1-ylmethyl]-pyridin-2-ylamine

The title compound was prepared in analogy to the procedures describedin Steps 100.1-100.2 but using 1-(4-methoxybenzyl)piperazine in Step100.2: 313.3 [M+H]⁺.

Example 1068-(2,6-Dichloro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid{5-[4-(2-hydroxy-ethyl)-piperazin-1-ylmethyl]-pyridin-2-yl}-amide

2-Iodoethanol (26 μL, 0.33 mmol, 10 equiv) was added to a mixture of8-(2,6-dichloro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid(5-piperazin-1-ylmethyl-pyridin-2-yl)-amide (Example 105) (18 mg, 0.033mmol) in CH₃CN (1 mL), under an argon atmosphere. The reaction mixturewas stirred for 14 h at rt, quenched by addition of a saturated aqueoussolution of NaHCO₃ (50 mL) and extracted with EtOAc. The organic layerwas washed with a saturated aqueous solution of NaHCO₃, dried (Na₂SO₄),filtered and concentrated. The residue was purified by silica gel columnchromatography (DCM/NH₃ ^(aq), 99:1→DCM/MeOH/NH₃ ^(aq), 96:3:1) toafford 15 mg of the title compound as a yellow solid. Title compound:ESI-MS: 596.6/598.4 [M+H]⁺; t_(R)=3.45 min (System 1); TLC: R_(f)=0.30(DCM/MeOH, 9:1).

Example 1078-(2,6-Dichloro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid[5-(3,3,4-trimethyl-piperazin-1-ylmethyl)-pyridin-2-yl]-amide

The title compound was prepared in analogy to the procedure described inStep 14.1 but using5-(3,3,4-trimethyl-piperazin-1-ylmethyl)-pyridin-2-ylamine (Step 107.1)and stirring the reaction mixture for 20 h at rt. The crude product waspurified by silica gel column chromatography (DCM/NH₃ ^(aq),99:1→DCM/MeOH/NH₃ ^(aq), 97:2:1) followed by trituration in Et₂O. Titlecompound: ESI-MS: 595.0/597.3 [M+H]⁺; t_(R)=4.40 min (System 1); TLC:R_(f)=0.36 (DCM/MeOH, 9:1).

Step 107.1: 5-(3,3,4-Trimethyl-piperazin-1-ylmethyl)-pyridin-2-ylamine

The title compound was prepared in analogy to the procedures describedin Steps 100.1-100.2 but using 1,2,2-trimethyl-piperazine (Step 107.2)in Step 100.2: 253.3 [M+H]⁺; TLC: R_(f)=0.09 (DCM/MeOH, 9:1).

Step 107.2: 1,2,2-Trimethyl-piperazine

LiAlH₄ (1M in THF, 47 mL, 47 mmol, 1.5 equiv) was added to a solution of3,3,4-trimethyl-piperazin-2-one (Step 107.3) (4.5 g, 32 mmol) in THF (50mL) at 50° C., under an argon atmosphere. The resulting mixture wasstirred for 2 h at 50° C., quenched by addition of acetone, filteredthrough a pad of celite and concentrated. The residue was purified bysilica gel column chromatography (DCM/MeOH/NH₃ ^(aq), 94:5:1) to afford1.9 g of the title compound as a yellow oil. Title compound: ESI-MS:129.1 [M+H]⁺.

Step 107.3: 3,3,4-Trimethyl-piperazin-2-one

A mixture of ethyl-2-bromoisobutyrate (14.6 g, 74.9 mmol), ethylenediamine (33 mL, 487 mmol, 6.5 equiv) and potassium carbonate (11.4 g,82.4 mmol, 1.1 equiv) in toluene (150 mL) was stirred for 22 h atreflux, cooled and filtered. The filtrate was concentrated and theresidue triturated in Et₂O to afford 6.3 g of3,3-dimethyl-piperazin-2-one as a white solid. Methyl iodide (4 mL, 64.0mmol, 1.3 equiv) was added dropwise to a suspension of3,3-dimethyl-piperazin-2-one (6.3 g, 49.2 mmol) and potassium carbonate(8.8 g, 64.0 mmol, 1.3 equiv) in DME (20 mL). The reaction mixture washeated to 45° C., stirred for 3 h, cooled and filtered, washing thefilter cake with DME. The filtrate was concentrated and the residuetriturated in DME to afford 2.8 g (batch 1) of the title compound as awhite solid. The filtrate from the trituration was concentrated and theresidue purified by silica gel column chromatography (DCM/MeOH, 9:1) toafford 1.75 g (batch 2) of the title compound as a white solid. Titlecompound: ESI-MS: 143.1 [M+H]⁺; TLC: R_(f)=0.25 (DCM/MeOH, 9:1).

Example 1088-(2,6-Dichloro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid[5-(3,3,4-trimethyl-piperazin-1-ylmethyl)-pyridin-2-yl]-amide

Intermediate 108 was prepared in analogy to the procedures described inStep 14.1 but using5-[4-(4-methoxy-benzyl)-3,3-dimethyl-piperazin-1-ylmethyl]-pyridin-2-ylamine(Step 108.1) and stirring the reaction mixture for 20 h at rt: ESI-MS:701.0 [M+H]⁺; t_(R)=4.88 min (System 1);

The title compound was prepared in analogy to the procedure described inExample 105. Title compound: ESI-MS: 581.0/583.2 [M+H]⁺; t_(R)=4.20 min(System 1); TLC: R_(f)=0.09 (DCM/MeOH, 9:1).

Step 108.1:5-[4-(4-Methoxy-benzyl)-3,3-dimethyl-piperazin-1-ylmethyl]-pyridin-2-ylamine

The title compound was prepared in analogy to the procedures describedin Steps 100.1-100.2 but using1-(4-methoxy-benzyl)-2,2-dimethyl-piperazine (Step 108.2) in Step 100.2:ESI-MS: 341.3 [M+H]⁺; TLC: R_(f)=0.30 (DCM/MeOH, 9:1).

Step 108.2: 1-(4-Methoxy-benzyl)-2,2-dimethyl-piperazine

LiAlH₄ (1M in THF, 27.8 mL, 27.8 mmol, 1.5 equiv) was added to asolution of 4-(4-methoxy-benzyl)-3,3-dimethyl-piperazin-2-one (Step108.3) (4.6 g, 18.5 mmol) in THF (100 mL) at 50° C., under an argonatmosphere. The resulting mixture was stirred for 2 h at 50° C.,quenched by sequential addition of H₂O (1 mL), 1 N NaOH (1 mL) and H₂O(3 mL), filtered through a pad of celite and concentrated to afford 4.0g of the title compound as a white solid: ESI-MS: 235.2 [M+H]⁺.

Step 108.3: 4-(4-Methoxy-benzyl)-3,3-dimethyl-piperazin-2-one

A mixture of 3,3-dimethyl-piperazin-2-one (Step 108.4) (3.7 g, 28.9mmol), 4-methoxybenzyl bromide (5.4 mL, 37.6 mmol, 1.3 equiv) andtriethylamine (5.2 mL, 37.6 mmol, 1.3 equiv) in DCM (60 mL) was stirredfor 48 h at rt. Additional 5.0 mL of 4-methoxybenzyl bromide were addedand the mixture was stirred for 72 h at rt, then concentrated. Theresidue was diluted with DCM/saturated aqueous solution of NaHCO₃. Theaqueous phase was separated and extracted with DCM. The organic phasewas washed with H₂O and brine, dried (Na₂SO₄), filtered andconcentrated. The residue was triturated in DCM to provide 3.95 g of thetitle compound as a white solid: ESI-MS: 249.2 [M+H]⁺; TLC: R_(f)=0.16(Hex/EtOAc, 2:3).

Step 108.4: 3,3-Dimethyl-piperazin-2-one

A solution of ethyl-2-bromoisobutyrate (24 mL, 161 mmol) in toluene (150mL) was added to a mixture of ethylene diamine (70 mL, 1046 mmol, 6.5equiv) and potassium carbonate (24.4 g, 177 mmol, 1.1 equiv) in toluene(150 mL). The reaction mixture was heated for 20 h at 115° C., cooledand filtered. The filtrate was concentrated and the residue trituratedin Et₂O to afford 14.2 g of the title compound as a yellow solid:ESI-MS: 129.1 [M+H]⁺.

Example 1098-(2,6-Dichloro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid[5-(2,2-dimethyl-piperazin-1-ylmethyl)-pyridin-2-yl]amide

Intermediate 109 was prepared in analogy to the procedure described inStep 14.1 but using5-[4-(4-methoxy-benzyl)-2,2-dimethyl-piperazin-1-ylmethyl]-pyridin-2-ylamine(Step 109.1) and stirring the reaction mixture for 20 h at rt: ESI-MS:701.0/583.2 [M+H]⁺; TLC: R_(f)=0.40 (DCM/MeOH, 9:1).

The title compound was prepared in analogy to the procedure described inExample 105. Title compound: ESI-MS: 581.0/582.8 [M+H]⁺; t_(R)=3.53 min(System 1); TLC: R_(f)=0.14 (DCM/MeOH, 9:1).

Step 109.1:5-[4-(4-Methoxy-benzyl)-2,2-dimethyl-piperazin-1-ylmethyl]-pyridin-2-ylamine

A mixture of{5-[4-(4-methoxy-benzyl)-2,2-dimethyl-piperazin-1-ylmethyl]-pyridin-2-yl}-carbamicacid tert-butyl ester (Step 109.2) (1.88 g, 4.3 mmol), a 4 N solution ofHCl in dioxane (25 mL) and MeOH (25 mL) was stirred for 22 h at rt. Thereaction mixture was allowed to cool, quenched by addition of asaturated aqueous solution of NaHCO₃ and extracted with DCM. The organiclayer was washed with a saturated aqueous solution of NaHCO₃, dried(Na₂SO₄), filtered and concentrated to provide 1.5 g of the titlecompound as a brown solid: ESI-MS: 341.3 [M+H]⁺;]⁺; t_(R)=1.72 min(System 1).

Step 109.2:{5-[4-(4-Methoxy-benzyl)-2,2-dimethyl-piperazin-1-ylmethyl]-pyridin-2-yl}-carbamicacid tert-butyl ester

A mixture of[5-(2,2-dimethyl-piperazin-1-ylmethyl)-pyridin-2-yl]carbamic acidtert-butyl ester (Step 109.3) (3.85 g, 12 mmol), 4-methoxybenzyl bromide(2.6 mL, 18 mmol, 1.5 equiv) and triethylamine (1.83 mL, 13.2 mmol, 1.1equiv) in DCM (25 mL) was stirred for 16 h at rt and concentrated. Theresidue was purified by silica gel column chromatography (DCM→DCM/MeOH,97:3) to afford 1.88 g of the title compound as a white solid. Titlecompound: ESI-MS: 441.3 [M+H]⁺; t_(R)=3.12 min (System 1).

Step 109.3: [5-(2,2-Dimethyl-piperazin-1-ylmethyl)-pyridin-2-yl]carbamicacid tert-butyl ester

LiAlH₄ (1M in THF, 78 mL, 78 mmol, 2 equiv) was added to a solution of[5-(2,2-dimethyl-3-oxo-piperazin-1-ylmethyl)-pyridin-2-yl]-carbamic acidtert-butyl ester (Step 109.4) (13 g, 39 mmol) in THF (150 mL) at 50° C.,under an argon atmosphere. The resulting mixture was stirred for 3 h at50° C., cooled to 0° C., quenched by addition of acetone, filteredthrough a pad of celite and the filtrate was concentrated. The residuewas purified by silica gel column chromatography (DCM/MeOH/NH₃ ^(aq),97.5:1.5:1) to afford 7.25 g of the title compound as a white solid.Title compound: ESI-MS: 321.3 [M+H]⁺; t_(R)=1.91 min (System 1); TLC:R_(f)=0.11 (DCM/MeOH, 9:1).

Step 109.4:[5-(2,2-Dimethyl-3-oxo-piperazin-1-ylmethyl)-pyridin-2-yl]-carbamic acidtert-butyl ester

A mixture of intermediate 100.2 (Step 100.2) (18.4 g, 64 mmol),3,3-dimethyl-piperazin-2-one (Step 108.4) (9 g, 70 mmol, 1.1 equiv) andCs₂CO₃ (27.1 g, 83.2 mmol, 1.3 equiv) in DMF (75 ml) was stirred for 12h at rt, quenched by addition of H₂O (500 mL) and filtered to afford14.5 g of the title compound as an off-white solid. Title compound:ESI-MS: 335.2 [M+H]⁺; t_(R)=2.22 min (System 1).

Example 1108-(2,6-Dichloro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid[5-(2,2,4-trimethyl-piperazin-1-ylmethyl)-pyridin-2-yl]-amide

The title compound was prepared in analogy to the procedure described inStep 14.1 but using5-[4-(4-methoxy-benzyl)-2,2-dimethyl-piperazin-1-ylmethyl]-pyridin-2-ylamine(Step 110.1) and stirring the reaction mixture for 20 h at rt. The crudeproduct was purified by silica gel column chromatography (DCM/MeOH/NH₃^(aq), 98:1:1) followed by trituration in Et₂O. Title compound: ESI-MS:595.0/597.2 [M+H]⁺; t_(R)=3.74 min (System 1); TLC: R_(f)=0.47(DCM/MeOH, 9:1).

Step 110.1: 5-(2,2,4-Trimethyl-piperazin-1-ylmethyl)-pyridin-2-ylamine

A mixture of[5-(2,2,4-trimethyl-piperazin-1-ylmethyl)-pyridin-2-yl]-carbamic acidtert-butyl ester (Step 110.2) (1.94 g, 5.8 mmol), a 4 N solution of HClin dioxane (20 mL) and MeOH (5 mL) was stirred for 12 h at rt andconcentrated. The residue was purified by silica gel columnchromatography (DCM/NH₃ ^(aq), 99:1→DCM/MeOH/NH₃ ^(aq), 95:4:1) toafford 1.02 g of the title compound as a white solid. Title compound:ESI-MS: 235.2 [M+H]⁺; TLC: R_(f)=0.11 (DCM/MeOH, 9:1).

Step 110.2:[5-(2,2,4-Trimethyl-piperazin-1-ylmethyl)-pyridin-2-yl]-carbamic acidtert-butyl ester

Methyl iodide (954 μL, 15.3 mmol, 1.3 equiv) was added dropwise to asuspension of[5-(2,2-dimethyl-piperazin-1-ylmethyl)-pyridin-2-yl]-carbamic acidtert-butyl ester (Step 109.3) (3.8 g, 11.8 mmol) and potassium carbonate(2.13 g, 15.4 mmol, 1.3 equiv) in DME (25 mL). The reaction mixture washeated to 50° C., stirred for 2 h, allowed to cool, quenched by additionof a H₂O and extracted with DCM. The organic layer was washed with asaturated aqueous solution of NaHCO₃, dried (Na₂SO₄), filtered andconcentrated. The residue was purified by silica gel columnchromatography (DCM/MeOH/NH₃ ^(aq), 98:1:1) to afford 1.94 g of thetitle compound as an off-white solid. Title compound: ESI-MS: 335.3[M+H]⁺; TLC: R_(f)=0.31 (DCM/MeOH, 9:1).

Example 1118-(2,6-Dichloro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid(6-piperazin-1-ylmethyl-pyridin-3-yl)-amide

Intermediate 111 was prepared in analogy to the procedure described inStep 14.1 but using6-[4-(4-methoxy-benzyl)-piperazin-1-ylmethyl]-pyridin-3-ylamine (Step111.1) and stirring the reaction mixture for 14 h at rt: ESI-MS: 673.0[M+H]⁺; t_(R)=3.88 min (System 1).

The title compound was prepared in analogy to the procedure described inExample 105 but stirring the reaction mixture for 1 h at 120° C.:ESI-MS: 553.0/554.8 [M+H]⁺; t_(R)=3.34 min (System 1); TLC: R_(f)=0.05(DCM/MeOH, 9:1).

Step 111.1:6-[4-(4-Methoxy-benzyl)-piperazin-1-ylmethyl]-pyridin-3-ylamine

A suspension of1-(4-methoxy-benzyl)-4-(5-nitro-pyridin-2-ylmethyl)-piperazine (Step111.2) (0.635 g, 1.85 mmol) and Raney Nickel (0.150 g) in MeOH/THF (1:1,v/v; 50 mL) was stirred for 24 h at rt, under a hydrogen atmosphere. Themixture was filtered through a pad of celite and the filtrate wasconcentrated. The residue was purified by silica gel columnchromatography (DCM/MeOH/NH₃ ^(aq), 98:1:1) to afford 439 mg of thetitle compound as a white solid. Title compound: ESI-MS: 313.3 [M+H]⁺;t_(R)=1.40 min (System 1); TLC: R_(f)=0.18 (DCM/MeOH, 9:1).

Step 111.2:1-(4-Methoxy-benzyl)-4-(5-nitro-pyridin-2-ylmethyl)-piperazine

The title compound was prepared in analogy to the procedures describedin Steps 39.1-39.2 but using 1-(4-methoxybenzyl)piperazine, 3 equiv ofsodium triacetoxyborohydride and stirring the reaction mixture for 20 hat rt, in Step 39.2. Title compound: ESI-MS: 343.2 [M+H]⁺; t_(R)=2.50min (System 1); TLC: R_(f)=0.40 (DCM/MeOH, 9:1).

Example 1128-(2,6-Dichloro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid[6-(3,3-dimethyl-piperazin-1-ylmethyl)-pyridin-3-yl]-amide

Intermediate 112 was prepared in analogy to the procedure described inStep 14.1 but using6-[4-(4-methoxy-benzyl)-3,3-dimethyl-piperazin-1-ylmethyl]-pyridin-3-ylamine(Step 112.1) and stirring the reaction mixture for 3 h at rt: ESI-MS:700.9 [M+H]⁺; t_(R)=4.00 min (System 1); TLC: R_(f)=0.45 (DCM/MeOH,9:1).

The title compound was prepared in analogy to the procedure described inExample 105 but stirring the reaction mixture for 1 h at 120° C.:ESI-MS: 581.0/583.2 [M+H]⁺; t_(R)=3.47 min (System 1); TLC: R_(f)=0.11(DCM/MeOH, 9:1).

Step 112.1:6-[4-(4-Methoxy-benzyl)-3,3-dimethyl-piperazin-1-ylmethyl]-pyridin-3-ylamine

A suspension of1-(4-methoxy-benzyl)-2,2-dimethyl-4-(5-nitro-pyridin-2-ylmethyl)-piperazine(Step 112.2) (0.640 g, 1.72 mmol) and Raney Nickel (0.150 g) in MeOH/THF(1:1, v/v; 50 mL) was stirred for 20 h at rt, under a hydrogenatmosphere. The mixture was filtered through a pad of celite and thefiltrate was concentrated. The residue was purified by silica gel columnchromatography (DCM/NH₃ ^(aq), 99:1→DCM/MeOH/NH₃ ^(aq), 97:2:1) toafford 455 mg of the title compound as a yellow foam. Title compound:ESI-MS: 341.3 [M+H]⁺; t_(R)=1.71 min (System 1); TLC: R_(f)=0.30(DCM/MeOH, 9:1).

Step 112.2:1-(4-Methoxy-benzyl)-2,2-dimethyl-4-(5-nitro-pyridin-2-ylmethyl)-piperazine

A mixture of methanesulfonic acid 5-nitro-pyridin-2-ylmethyl ester (Step112.3) (0.5 g, 2.16 mmol), 1-(4-methoxy-benzyl)-2,2-dimethyl-piperazine(Step 108.2) (0.655 g, 2.8 mmol, 1.3 equiv), cesium carbonate (0.845 g,2.6 mmol, 1.2 equiv), and DMF (4 ml) was stirred for 5 h at rt, quenchedby addition of a saturated aqueous solution of NaHCO₃ and extracted withEtOAc. The organic phase was washed with a saturated aqueous solution ofNaHCO₃, dried (Na₂SO₄), filtered and concentrated. The residue waspurified by silica gel column chromatography (DCM→DCM/MeOH, 99:1) toprovide 0.642 g of the title compound as a red solid: ESI-MS: 371.2[M+H]⁺; t_(R)=3.18 min (System 1); TLC: R_(f)=0.44 (DCM/MeOH, 9:1).

Step 112.3: Methanesulfonic acid 5-nitro-pyridin-2-ylmethyl ester

Methanesulfonic anhydride (1.79 g, 10.3 mmol, 1.1 equiv) was addedportionwise to a cold (5° C.) mixture of (5-nitro-pyridin-2-yl)-methanol(Step 112.4) (1.44 g, 9.4 mmol) and triethylamine (1.57 mL, 11.3 mmol,1.2 equiv) in DCM (20 mL), under an argon atmosphere. The reactionmixture was allowed to stir for 0.5 h at 5° C., quenched with H₂O andextracted with DCM. The organic phase was washed with H₂O, dried(Na₂SO₄), filtered and concentrated to provide 2.16 g of the titlecompound as a brown solid:: ESI-MS: 231.1 [M−H]⁻; t_(R)=2.85 min (System1).

Step 112.4: (5-Nitro-pyridin-2-yl)-methanol

Diisobutylaluminium hydride (1 M in DCM, 41.6 mL, 41.6 mmol, 1.3 equiv)was added dropwise to a cold (−78° C.) solution of5-nitro-pyridine-2-carboxylic acid ethyl ester (Step 39.4) (6.4 g, 32mmol) in DCM (120 mL), under an argon atmosphere. The reaction mixturewas allowed to warm to rt, quenched by addition of an aqueous solutionof potassium sodium tartrate, diluted with DCM and H₂O, and filteredthrough a pad of celite. The filtrate was extracted several times withDCM. The organic phase was washed with brine, dried (Na₂SO₄), filteredand concentrated. The residue was purified by silica gel columnchromatography (Hex/EtOAc, 9:1→1:1) to provide 1.44 g of the titlecompound: ESI-MS: 153.1 [M−H]⁻.

Example 1138-(2,6-Dichloro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid[6-(3,3,4-trimethyl-piperazin-1-ylmethyl)-pyridin-3-yl]-amide

Methyl iodide (15 μL, 0.24 mmol, 1.2 equiv) was added to a mixture of8-(2,6-dichloro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid[6-(3,3-dimethyl-piperazin-1-ylmethyl)-pyridin-3-yl]-amide (Example 112)(115 mg, 0.2 mmol) and potassium carbonate (33 mg, 0.24 mmol, 1.2 equiv)in CH₃CN (4 mL). The reaction mixture was stirred for 72 h at rt,quenched by addition of a saturated aqueous solution of NaHCO₃ andextracted with EtOAc. The organic layer was washed with a saturatedaqueous solution of NaHCO₃, dried (Na₂SO₄), filtered and concentrated.The residue was purified by silica gel column chromatography (DCM/NH₃^(aq), 99:1→DCM/MeOH/NH₃ ^(aq), 96:3:1) followed by trituration id Et₂Oto afford 27 mg of the title compound as a yellow solid. Title compound:ESI-MS: 595.1/596.6 [M+H]⁺; t_(R)=3.54 min (System 1); TLC: R_(f)=0.17(DCM/MeOH, 9:1).

Example 1148-(2,6-Dichloro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid[6-(2,2,4-trimethyl-piperazin-1-ylmethyl)-pyridin-3-yl]-amide

The title compound was prepared in analogy to the procedure described inStep 14.1 but using6-(2,2,4-trimethyl-piperazin-1-ylmethyl)-pyridin-3-ylamine (Step 114.1)and stirring the reaction mixture for 14 h at rt. ESI-MS: 595.1/597.2[M+H]⁺; t_(R)=3.52 min (System 1); TLC: R_(f)=0.37 (DCM/MeOH, 9:1).

Step 114.1: 6-(2,2,4-Trimethyl-piperazin-1-ylmethyl)-pyridin-3-ylamine

The title compound was prepared in analogy to the procedures describedin Steps 112.1-112.2 but using 1,3,3-trimethyl-piperazine (Step 114.2)in Step 112.2: ESI-MS: 235.3 [M+H]⁺; TLC: R_(f)=0.13 (DCM/MeOH, 9:1).

Step 114.2: 1,3,3-Trimethyl-piperazine

LiAlH₄ (1M in THF, 32.5 mL, 32.5 mmol, 1.5 equiv) was added to asolution of 3,3-dimethyl-2-oxo-piperazine-1-carboxylic acid tert-butylester (Step 114.3) (4.95 g, 21.7 mmol) in THF (100 mL) at 50° C., underan argon atmosphere. The resulting mixture was stirred for 3 h at 50°C., cooled to 0° C., quenched by addition of acetone and concentrated.The residue was purified by silica gel column chromatography(DCM/MeOH/NH₃ ^(aq), 94:5:1) to afford 2 g of the title compound as ayellow oil. Title compound: ESI-MS: 129.1.

Step 114.3: 3,3-Dimethyl-2-oxo-piperazine-1-carboxylic acid tert-butylester

A solution of di-tert-butyl dicarbonate (9.3 g, 42.5 mmol, 1.1 equiv) inDCM (20 mL) was added dropwise to a solution of3,3-dimethyl-piperazin-2-one (Step 108.4) (4.95 g, 38.7 mmol) and DMAP(457 mg, 3.9 mmol, 0.1 equiv) in DCM (20 mL) at rt, under an argonatmosphere. The reaction mixture was stirred for 20 h at rt, quenched byaddition of a saturated aqueous solution of NaHCO₃ (100 mL) andextracted with DCM. The organic phase was washed with a saturatedaqueous solution of NaHCO₃, dried (Na₂SO₄), filtered and concentrated.The residue was purified by silica gel column chromatography(DCM/MeOH/NH₃ ^(aq), 98:1:1) to afford 4.97 g of the title compound as acolorless oil. Title compound: ESI-MS: 227.2 [M−H]⁻; t_(R)=1.62 min(System 1).

Example 115 8-(3,5-Dimethoxy-phenyl)-quinoxaline-5-carboxylic acid[5-(4-ethyl-piperazin-1-ylmethyl)-pyridin-2-yl]-amide

Trimethyl aluminum (2 M in toluene, 0.37 mL, 0.74 mmol, 2.5 equiv) wasadded to a mixture of 8-(3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylicacid ethyl ester (Step 115.1) (100 mg, 0.30 mmol) and5-(4-ethyl-piperazin-1-ylmethyl)-pyridin-2-ylamine (Step 26.1; purifiedby column chromatography) (78 mg, 0.36 mmol, 1.2 equiv) in toluene (2mL). The reaction mixture was stirred for 1 h at rt, heated to reflux,stirred for 3 h, allowed to cool, poured onto EtOAc and H₂O, andfiltered through a pad of celite. The filtrate was extracted with EtOAc.The organic phase was washed with H₂O and brine, dried (Na₂SO₄),filtered and concentrated. The residue was purified by silica gel columnchromatography (DCM/MeOH/NH₃ ^(aq), 94:5:1) followed by reverse-phasepreparative HPLC to afford 54 mg of the title compound as a pale yellowsolid. Title compound: ESI-MS: 513.2 [M+H]⁺; t_(R)=3.54 min (System 1);TLC: R_(f)=0.29 (DCM/MeOH/NH₃ ^(aq), 94:5:1).

Step 115.1: 8-(3,5-Dimethoxy-phenyl)-quinoxaline-5-carboxylic acid ethylester

A mixture of 8-(3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid(Step 1.2) (10 g), H₂SO₄ conc. (3 mL) and EtOH (500 mL) was stirred atreflux for 7 h, allowed to cool and concentrated. The residue wasdiluted in EtOAc and a saturated aqueous solution of NaHCO₃. The aqueousphase was separated and extracted with EtOAc. The combined organiclayers were washed with H₂O and brine, dried (Na₂SO₄), filtered andconcentrated to afford 10.1 g of the title compound as a beige solid.Title compound: ESI-MS: 339.2 [M−H]⁻; t_(R)=4.72 min (System 1).

Example 116 8-(3,5-Dimethoxy-phenyl)-quinoxaline-5-carboxylic acid{5-[4-(4-methoxy-benzyl)-piperazin-1-ylmethyl]-pyridin-2-yl}-amide

The title compound was in analogy to the procedure described in Example115 but using5-[4-(4-methoxy-benzyl)-piperazin-1-ylmethyl]-pyridin-2-ylamine (Step105.1). The residue was purified by silica gel column chromatography(DCM/MeOH/NH₃ ^(aq), 94:5:1) to afford 54 mg of the title compound as ayellow foam. Title compound: ESI-MS: 605.1 [M+H]⁺; t_(R)=3.98 min(System 1).

Example 117 8-(3,5-Dimethoxy-phenyl)-quinoxaline-5-carboxylic acid{5-[4-(4-methoxy-benzyl)-piperazin-1-ylmethyl]-pyridin-2-yl}-amide

α-Chloroethyl chloroformate (19 μL, 0.17 mmol) was added to a cold (−78°C.) solution of 8-(3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid{5-[4-(4-methoxy-benzyl)-piperazin-1-ylmethyl]pyridin-2-yl}-amide(Example 116) (103 mg, 0.17 mmol) in THF (2 mL). The reaction mixturewas stirred for 1 h at −78° C., quenched by addition of MeOH andconcentrated. The residue was dissolved in MeOH (5 mL), heated to refluxfor 3 h, allowed to cool. The resulting solid was collected byfiltration, diluted in DCM and a saturated aqueous solution of NaHCO₃,and extracted with DCM. The organic phase was dried (Na₂SO₄), filteredand concentrated. The residue was purified by silica gel columnchromatography (DCM/MeOH/NH₃ ^(aq), 91.5:7.5:1) followed by triturationin Et₂O to afford 28 mg of the title compound as a white solid. Titlecompound: ESI-MS: 485.2 [M+H]⁺; t_(R)=3.80 min (System 1); TLC:R_(f)=0.10 (DCM/MeOH/NH₃ ^(aq), 91.5:7.5:1).

Example 1188-(2,6-Dichloro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid{5-[(carbamoylmethyl-methyl-amino)-methyl]-pyridin-2-yl}-amide

The title compound was prepared in analogy to the procedure described inStep 14.1 but using2-[(6-amino-pyridin-3-ylmethyl)-methyl-amino]-acetamide (Step 118.1) andstirring the reaction mixture for 14 h at rt. Title compound: ESI-MS:555.0/556.8 [M+H]⁺; t_(R)=3.72 min (System 1); TLC: R_(f)=0.40(DCM/MeOH, 9:1).

Step 118.1: 2-[(6-Amino-pyridin-3-ylmethyl)-methyl-amino]-acetamide

The title compound was prepared in analogy to the procedures describedin Steps 100.1-100.2 but using 2-(methylamino)-acetamide hydrochloridein Step 100.2: 195.1 [M+H]⁺; TLC: R_(f)=0.12 (DCM/MeOH/NH₃ ^(aq),89:10:1).

Example 1198-(2,6-Dichloro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid{5-[)dimethylcarbamoylmethyl-methyl-amino)-methyl]-pyridin-2-yl}-amide

The title compound was prepared in analogy to the procedure described inStep 14.1 but using2-[(6-amino-pyridin-3-ylmethyl)-methyl-amino]-N,N-dimethyl-acetamide(Step 119.1) and stirring the reaction mixture for 72 h at rt. Titlecompound: ESI-MS: 583.0/585.2 [M+H]⁺; t_(R)=4.02 min (System 1); TLC:R_(f)=0.36 (DCM/MeOH, 9:1).

Step 119.1:2-[(6-Amino-pyridin-3-ylmethyl)-methyl-amino]-N,N-dimethyl-acetamide

The title compound was prepared in analogy to the procedures describedin Steps 100.1-100.2 but using N,N-dimethyl-2-(methylamino)-acetamide inStep 100.2: 223.2 [M+H]⁺; TLC: R_(f)=0.31 (DCM/MeOH/NH₃ ^(aq), 89:10:1).

Example 1208-(2,6-Dichloro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid(5-imidazol-1-ylmethyl-pyridin-2-yl)-amide

The title compound was prepared in analogy to the procedure described inStep 14.1 but using 5-imidazol-1-ylmethyl-pyridin-2-ylamine (Step 120.1)and stirring the reaction mixture for 20 h at rt. Title compound:ESI-MS: 535.0/536.8 [M+H]⁺; t_(R)=4.00 min (System 1); TLC: R_(f)=0.35(DCM/MeOH, 9:1).

Step 120.1: 5-Imidazol-1-ylmethyl-pyridin-2-ylamine

The title compound was prepared in analogy to the procedures describedin Steps 100.1-100.2 but using imidazole in Step 100.2: 175.1 [M+H]⁺;TLC: R_(f)=0.24 (DCM/MeOH, 9:1).

Example 1218-(2,6-Dichloro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid[1-(2-dimethylamino-ethyl)-1H-pyrrol-3-yl]-amide

The title compound was prepared in analogy to the procedure described inStep 14.1 but using 1-(2-dimethylamino-ethyl)-1H-pyrrol-3-ylamine (Step121.1) and stirring the reaction mixture for 14 h at rt. Title compound:ESI-MS: 514.0/515.9 [M+H]⁺; t_(R)=3.86 min (System 1); TLC: R_(f)=0.22(DCM/MeOH, 9:1).

Step 121.1: 1-(2-Dimethylamino-ethyl)-1H-pyrrol-3-ylamine

A suspension of dimethyl-[2-(3-nitro-pyrrol-1-yl)-ethyl]-amine (Step121.2) (650 mg, 3.55 mmol) and Raney Nickel (300 mg) in MeOH/THF (1:1,v/v; 150 mL) was stirred for 7 h at rt, under a hydrogen atmosphere. Themixture was filtered through a pad of celite and the filtrate wasconcentrated. The residue was purified by silica gel columnchromatography (DCM/MeOH/NH₃ ^(aq), 98:1:1→93:6:1) to afford 440 mg ofthe title compound as a red oil. Title compound: ESI-MS: 154.1 [M+H]⁺;TLC: R_(f)=0.02 (DCM/MeOH, 9:1).

Step 121.2: Dimethyl-[2-(3-nitro-pyrrol-1-yl)-ethyl]-amine

A mixture of 3-nitropyrrole (500 mg, 4.46 mmol), cesium carbonate (3.63g, 11.2 mmol, 2.5 equiv), 1-chloro-2-dimethylaminoethane (835 mg, 5.8mmol, 1.3 equiv) and DMF (5 mL) was stirred for 16 h at rt. The reactionmixture was quenched by addition of a saturated aqueous solution ofNaHCO₃ and extracted with DCM/MeOH (9:1, v/v). The organic phase waswashed with a saturated aqueous solution of NaHCO₃, dried (Na₂SO₄),filtered and concentrated. The residue was purified by silica gel columnchromatography (DCM DCM/MeOH, 97:3) to afford 656 mg of the titlecompound as a yellow oil. Title compound: ESI-MS: 184.1 [M+H]⁺; TLC:R_(f)=0.38 (DCM/MeOH, 9:1).

Example 1228-(2,6-Dichloro-3,5-dimethoxy-phenyl)-2,3-dimethyl-quinoxaline-5-carboxylicacid [5-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-yl]-amide

The title compound was prepared in analogy to the procedure described inStep 14.1 but using8-(2,6-dichloro-3,5-dimethoxy-phenyl)-2,3-dimethyl-quinoxaline-5-carboxylicacid (Step 122.1), 5-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-ylamine(Example 31; purified by silica gel column chromatography), and stirringthe reaction mixture 18 h at rt. Title compound: ESI-MS: 595.0 [M+H]⁺;t_(R)=3.86 min (System 1); TLC: R_(f)=0.15 (DCM/MeOH/NH₃ ^(aq), 94:5:1).

Step 122.1:8-(2,6-Dichloro-3,5-dimethoxy-phenyl)-2,3-dimethyl-quinoxaline-5-carboxylicacid

The title compound was prepared in analogy to the procedures describedin Steps 1.1-1.3 but using5-bromo-8-(3,5-dimethoxy-phenyl)-2,3-dimethyl-quinoxaline (Step 122.2)in Step 1.3. Title compound: ESI-MS: 407.1/408.9 [M+H]⁺.

Step 122.2: 5-Bromo-8-(3,5-dimethoxy-phenyl)-2,3-dimethyl-quinoxaline

A mixture of 4-bromo-3′,5′-dimethoxy-biphenyl-2,3-diamine (Step 85.7) (3g, 9.3 mmol) and 2,3-butanedione (1 mL, 11.1 mmol, 1.2 equiv) in EtOH(60 mL) was stirred at reflux for 2 h, allowed to cool to rt and stirredfor 16 h. Additional 2,3-butanedione (0.4 ml) was added. The reactionmixture was stirred at reflux for 2 h, allowed to cool and concentratedto half of the initial volume. The resulting yellow precipitate wascollected vacuum filtration providing 2.9 g of the title compound:ES-MS: 373.1/375.0 [M+H]⁺; t_(R)=5.60 min (System 1).

Example 1238-(2,6-Dichloro-3,5-dimethoxy-phenyl)-2,3-dimethyl-quinoxaline-5-carboxylicacid (5-piperazin-1-ylmethyl-pyridin-2-yl)-amide

Intermediate 123 was prepared in analogy to the procedure described inStep 14.1 but using5-[4-(4-methoxy-benzyl)-piperazin-1-ylmethyl]-pyridin-2-ylamine (Step105.1) and stirring the reaction mixture for 18 h at rt: ESI-MS: 701.0[M+H]⁺; TLC: R_(f)=0.54 (DCM/MeOH/NH₃ ^(aq), 94:5:1).

The title compound was prepared in analogy to the procedure described inExample 105 but stirring the reaction mixture for 0.5 h at 120° C. in amicrowave apparatus. Title compound: ESI-MS: 581.0/583.2 [M+H]⁺;t_(R)=3.69 min (System 1); TLC: R_(f)=0.10 (DCM/MeOH/NH₃ ^(aq),91.5:7.5:1).

Example 1248-(2,6-Difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid[5-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-yl]-amide

The title compound was prepared in analogy to the procedure described inExample 115 but using8-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acidethyl ester (Step 124.1) and5-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-ylamine (Example 31;purified by silica gel column chromatography). Title compound: ESI-MS:535.1 [M+H]⁺; t_(R)=3.45 min (System 1); TLC: R_(f)=0.19 (DCM/MeOH/NH₃^(aq), 94:5:1).

Step 124.1:8-(2,6-Difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acidethyl ester

2,6-dichloro-1-fluoropyridinium tetrafluoroborate (13.9 g, 54.6 mmol,1.8 equiv) was added to a cold (−5° C.) solution of8-(3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid ethyl ester (Step115.1) (10.1 g, 29.9 mmol) in CH₃CN (100 mL). The reaction mixture wasallowed to warm to rt overnight, cooled to 5° C. and quenched byaddition of a saturated aqueous solution of NaHCO₃ (20 mL). The organicsolvent was removed in vacuo and the residual layer was diluted in EtOAcand a saturated aqueous solution of NaHCO₃. The aqueous phase wasseparated and extracted with EtOAc. The combined organic layers werewashed with H₂O and brine, dried (Na₂SO₄), filtered and concentrated.Several purifications by silica gel column chromatography (DCM/Hex/Et₂₀,1:3:6) provide 2.93 g of the title compound as a white solid. Titlecompound: ESI-MS: 375.1 [M+H]⁺; t_(R)=4.60 min (System 1); TLC:R_(f)=0.19 (DCM/Hex/Et₂₀, 1:3:6).

Example 1258-(2,6-Difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid(5-piperazin-1-ylmethyl-pyridin-2-yl)-amide

Intermediate 125 was prepared in analogy to the procedure described inExample 115 but using8-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acidethyl ester (Step 124.1),5-[4-(4-methoxy-benzyl)-piperazin-1-ylmethyl]-pyridin-2-ylamine (Step105.1), 2 equiv of trimethyl aluminum, stirring the reaction mixture for9 h at 80° C., pouring it onto a saturated aqueous solution of NaHCO₃and DCM: ESI-MS: 641.0 [M+H]⁺; TLC: R_(f)=0.61 (DCM/MeOH/NH₃ ^(aq),94:5:1).

The title compound was prepared in analogy to the procedure described inExample 105 but stirring the reaction mixture for 0.5 h at 120° C.:ESI-MS: 521.1 [M+H]⁺; t_(R)=3.30 min (System 1); TLC: R_(f)=0.10(DCM/MeOH/NH₃ ^(aq), 91.5:7.5:1).

Example 1268-(2,6-Difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid[5-(3,3,4-trimethyl-piperazin-1-ylmethyl)-pyridin-2-yl]-amide

The title compound was prepared in analogy to the procedure described inExample 115 but using8-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acidethyl ester (Step 124.1),5-(3,3,4-trimethyl-piperazin-1-ylmethyl)-pyridin-2-ylamine (Step 107.1),stirring the reaction mixture for 15 min at reflux, pouring it onto asaturated aqueous solution of NaHCO₃ and DCM. Title compound: ESI-MS:563.1 [M+H]⁺; t_(R)=3.72 min (System 1); TLC: R_(f)=0.33 (DCM/MeOH/NH₃^(aq), 94:5:1).

Example 1278-(2,6-Difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid(4-dimethylaminomethyl-1H-imidazol-2-yl)-amide

The title compound was prepared in analogy to the procedures describedin Example 14 but using8-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acidethyl ester (Step 124.1), Raney nickel and MeOH/THF (1:1) instead ofpalladium on carbon and MeOH in Step 14.2,dimethyl-(2-nitro-1H-imidazol-4-ylmethyl)-amine (Step 22.1) instead of2-nitroimidazole in Step 14.3. The title compound: ESI-MS: 469.1 [M+H]⁺;t_(R)=3.15 min (System 1); TLC: R_(f)=0.22 (DCM/MeOH/NH₃ ^(aq),91.5:7.5:1).

Example 1288-(2,6-Difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid[5-(2,2,4-trimethyl-piperazin-1-ylmethyl)-pyridin-2-yl]-amide

The title compound was prepared in analogy to the procedures describedin Example 115 but using8-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acidethyl ester (Step 124.1),5-(2,2,4-trimethyl-piperazin-1-ylmethyl)-pyridin-2-ylamine (Step 110.1),1.5 equiv of trimethyl aluminum, stirring the reaction mixture for 6 hat 80° C. and pouring it onto a saturated aqueous solution of NaHCO₃ andDCM. Title compound: ESI-MS: 563.1 [M+H]⁺; t_(R)=3.55 min (System 1);TLC: R_(f)=0.08 (DCM/MeOH, 95:5).

Example 1298-(2,6-Difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid[5-(2,2-dimethyl-piperazin-1-ylmethyl)-pyridin-2-yl]-amide

Intermediate 129 was prepared in analogy to the procedure described inExample 115 but using8-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acidethyl ester (Step 124.1),5-[4-(4-methoxy-benzyl)-2,2-dimethyl-piperazin-1-ylmethyl]-pyridin-2-ylamine(Step 109.1), 1.5 equiv of trimethyl aluminum, and stirring the reactionmixture for 5 h at 80° C.: ESI-MS: 669.0 [M+H]⁺; TLC: R_(f)=0.24(DCM/MeOH/NH₃ ^(aq), 94:5:1).

The title compound was prepared in analogy to the procedure described inExample 105 but stirring the reaction mixture for 0.5 h at 120° C.:ESI-MS: 549.1 [M+H]⁺; t_(R)=3.37 min (System 1); TLC: R_(f)=0.22(DCM/MeOH/NH₃ ^(aq), 91.5:7.5:1).

Example 1308-(2,6-Difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid[5-(3,3-dimethyl-piperazin-1-ylmethyl)-pyridin-2-yl]-amide

Intermediate 130 was prepared in analogy to the procedure described inExample 115 but using8-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acidethyl ester (Step 124.1),5-[4-(4-methoxy-benzyl)-3,3-dimethyl-piperazin-1-ylmethyl]-pyridin-2-ylamine(Step 108.1), 1.5 equiv of trimethyl aluminum, and stirring the reactionmixture for 5 h at 80° C.: ESI-MS: 669.0 [M+H]⁺; t_(R)=4.26 min (System1); TLC: R_(f)=0.13 (DCM/MeOH, 95:5). The title compound was prepared inanalogy to the procedure described in Example 105 but stirring thereaction mixture for 0.5 h at 120° C.: ESI-MS: 549.1 [M+H]⁺; t_(R)=3.55min (System 1); TLC: R_(f)=0.11 (DCM/MeOH/NH₃ ^(aq), 91.5:7.5:1).

Example 1318-(2,6-Difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid[6-(2,2,4-trimethyl-piperazin-1-ylmethyl)-pyridin-3-yl]amide

The title compound was prepared in analogy to the procedures describedin Example 115 but using8-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acidethyl ester (Step 124.1),6-(2,2,4-trimethyl-piperazin-1-ylmethyl)-pyridin-3-ylamine (Step 114.1),1.5 equiv of trimethyl aluminum, stirring the reaction mixture for 2 hat 80° C. and pouring it onto a saturated aqueous solution of NaHCO₃ andDCM. Title compound: ESI-MS: 563.2 [M+H]⁺; t_(R)=3.36 min (System 1);TLC: R_(f)=0.22 (DCM/MeOH/NH₃ ^(aq), 94:5:1).

Example 1328-(2,6-Difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid(6-piperazin-1-ylmethyl-pyridin-3-yl)-amide

Intermediate 132 was prepared in analogy to the procedure described inExample 115 but using8-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acidethyl ester (Step 124.1),6-[4-(4-methoxy-benzyl)-piperazin-1-ylmethyl]-pyridin-3-ylamine (Step111.1), 1.5 equiv of trimethyl aluminum, stirring the reaction mixturefor 0.5 h at 80° C. and pouring it onto a saturated aqueous solution ofNaHCO₃ and DCM: ESI-MS: 641.1 [M+H]⁺; t_(R)=3.72 min (System 1); TLC:R_(f)=0.22 (DCM/MeOH/NH₃ ^(aq), 94:5:1).

The title compound was prepared in analogy to the procedure described inExample 105 but stirring the reaction mixture for 0.5 h at 120° C.:ESI-MS: 521.1 [M+H]⁺; t_(R)=3.21 min (System 1); TLC: R_(f)=0.06(DCM/MeOH/NH₃ ^(aq), 91.5:7.5:1).

Example 1338-(2,6-Difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid[5-(3-oxo-piperazin-1-ylmethyl)-pyridin-2-yl]-amide

The title compound was prepared in analogy to the procedure described inExample 115 but using8-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acidethyl ester (Step 124.1), 4-(6-amino-pyridin-3-ylmethyl)-piperazin-2-one(Step 103.1), 1.5 equiv of trimethyl aluminum, stirring the reactionmixture for 7 h at 80° C. and pouring it onto a saturated aqueoussolution of NaHCO₃ and DCM. The title compound: ESI-MS: 535.1 [M+H]⁺;t_(R)=3.50 min (System 1); TLC: R_(f)=0.16 (DCM/MeOH/NH₃ ^(aq), 94:5:1).

Example 1348-(2,6-Difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid(5-{[(2-dimethylamino-ethyl)-methyl-amino]-methyl}-pyridin-2-yl)-amide

The title compound was prepared in analogy to the procedure described inExample 115 but using8-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acidethyl ester (Step 124.1),N-(6-amino-pyridin-3-ylmethyl)-N,N′,N′-trimethyl-ethane-1,2-diamine(prepared as described in Example 26 but usingN,N,N′-trimethyl-ethane-1,2-diamine in Step 26.2 and purified by columnchromatography), 1.5 equiv of trimethyl aluminum, stirring the reactionmixture for 5 h at 80° C. and pouring it onto a saturated aqueoussolution of NaHCO₃ and DCM. The title compound: ESI-MS: 537.1 [M+H]⁺;t_(R)=3.31 min (System 1); TLC: R_(f)=0.13 (DCM/MeOH, 95:5).

Example 1358-(2,6-Difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid(4-morpholin-4-ylmethyl-1H-imidazol-2-yl)-amide

The title compound was prepared in analogy to the procedures describedin Example 14 but stirring the reaction mixture for 2 h at 70° C. andusing 8-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylicacid ethyl ester (Step 124.1).4-(2-Nitro-1H-imidazol-4-ylmethyl)-morpholine (Step 23.1) was usedinstead of 2-nitroimidazole in Step 14.3, and Raney nickel and MeOH/THF(1:1) instead of palladium on carbon and MeOH in Step 14.2. The titlecompound: ESI-MS: 511.1 [M+H]⁺; t_(R)=3.21 min (System 1); TLC:R_(f)=0.34 (DCM/MeOH/NH₃ ^(aq), 94:5:1).

Example 1368-(2,6-Difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid{5-[(carbamoylmethyl-methyl-amino)-methyl]-pyridin-2-yl}-amide

The title compound was prepared in analogy to the procedure described inExample 115 but using8-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acidethyl ester (Step 124.1),2-[(6-amino-pyridin-3-ylmethyl)-methyl-amino]-acetamide (Step 118.1), 2equiv of trimethyl aluminum, stirring the reaction mixture for 22 h at80° C. and pouring it onto a saturated aqueous solution of NaHCO₃ andDCM. The title compound: ESI-MS: 523.1 [M+H]⁺; t_(R)=3.53 min (System1); TLC: R_(f)=0.16 (DCM/MeOH/NH₃ ^(aq), 94:5:1).

Example 1378-(2,6-Difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid{5-[(dimethylcarbamoylmethyl-methyl-amino)-methyl]-pyridin-2-yl}-amide

The title compound was prepared in analogy to the procedure described inExample 115 but using8-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acidethyl ester (Step 124.1),2-[(6-amino-pyridin-3-ylmethyl)-methyl-amino]-N,N-dimethyl-acetamide(Step 119.1), 2 equiv of trimethyl aluminum, stirring the reactionmixture for 6 h at 80° C. and pouring it onto a saturated aqueoussolution of NaHCO₃ and DCM. The title compound: ESI-MS: 551.1 [M+H]⁺;t_(R)=3.81 min (System 1); TLC: R_(f)=0.36 (DCM/MeOH/NH₃ ^(aq), 94:5:1).

Example 1388-(2,6-Difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid(5-imidazol-1-ylmethyl-pyridin-2-yl)-amide

The title compound was prepared in analogy to the procedure described inExample 115 but using8-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acidethyl ester (Step 124.1), 5-imidazol-1-ylmethyl-pyridin-2-ylamine (Step120.1), 2 equiv of trimethyl aluminum, stirring the reaction mixture for3 h at 80° C. and pouring it onto a saturated aqueous solution of NaHCO₃and DCM. The title compound: ESI-MS: 503.1 [M+H]⁺; t_(R)=3.76 min(System 1); TLC: R_(f)=0.47 (DCM/MeOH, 9:1).

Example 1398-(2,6-Difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid[1-(2-dimethylamino-ethyl)-1H-pyrrol-3-yl]-amide

The title compound was prepared in analogy to the procedure described inStep 14.1 but using8-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acidethyl ester (Step 124.1), 1-(2-dimethylamino-ethyl)-1H-pyrrol-3-ylamine(Step 121.1) and stirring the reaction mixture for 14 h at rt. Titlecompound: ESI-MS: 482.1 [M+H]⁺; t_(R)=3.66 min (System 1); TLC:R_(f)=0.21 (DCM/MeOH, 9:1).

Example 1408-(2,6-Difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid[5-(1,1-dioxo-thiomorpholin-4-ylmethyl)-pyridin-2-yl]-amide

The title compound was prepared in analogy to the procedure described inExample 115 but using8-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acidethyl ester (Step 124.1),5-(1,1-dioxothiomorpholin-4-ylmethyl)-pyridin-2-ylamine (Step 104.1), 2equiv of trimethyl aluminum, stirring the reaction mixture for 6 h at80° C. and pouring it onto a saturated aqueous solution of NaHCO₃ andDCM. Title compound: ESI-MS: 570.0 [M+H]⁺; t_(R)=3.86 min (System 1);TLC: R_(f)=0.10 (DCM/MeOH/NH₃ ^(aq), 94:5:1).

Example 1418-(2,6-Difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid[4-(4-methyl-piperazin-1-ylmethyl)-1H-imidazol-2-yl]-amide

The title compound was prepared in analogy to the procedures describedin Example 14 but using8-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acidethyl ester (Step 124.1), Raney nickel and MeOH/THF (1:1) instead ofpalladium on carbon and MeOH in Step 14.2, and1-methyl-4-(2-nitro-1H-imidazol-4-ylmethyl)-piperazine (Step 20.1)instead of 2-nitroimidazole in Step 14.3. Title compound: ESI-MS: 524.1[M+H]⁺; t_(R)=3.03 min (System 1); TLC: R_(f)=0.22 (DCM/MeOH/NH₃ ^(aq),94:5:1).

Example 1428-(2,6-Difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid[4-(3-oxo-piperazin-1-ylmethyl)-1H-imidazol-2-yl]-amide

The title compound was prepared in analogy to the procedures describedin Example 14 but using8-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acidethyl ester (Step 124.1), Raney nickel and MeOH/THF (1:1) instead ofpalladium on carbon and MeOH in Step 14.2, and4-(2-nitro-1H-imidazol-4-ylmethyl)-piperazin-2-one (Step 142.1) insteadof 2-nitroimidazole in Step 14.3. Title compound: ESI-MS: 524.1 [M+H]⁺;t_(R)=3.10 min (System 1); TLC: R_(f)=0.23 (DCM/MeOH, 9:1).

Step 142.1: 4-(2-Nitro-1H-imidazol-4-ylmethyl)-piperazin-2-one

The title compound was prepared in analogy to the procedures describedin Step 18.1 but using piperazin-2-one instead of diethyl amine, and itwas obtained as an impure sample which was used without furtherpurification.

Example 143 8-(2-Fluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylicacid [5-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-yl]-amide

The title compound was prepared in analogy to the procedure described inExample 115 but using8-(2-fluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid ethylester (Step 143.1), 5-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-ylamine(Example 31; purified by silica gel column chromatography), and stirringthe reaction mixture for 1 h at reflux. Title compound: ESI-MS: 517.1[M+H]⁺; t_(R)=3.37 min (System 1); TLC: R_(f)=0.11 (DCM/MeOH/NH₃ ^(aq),94:5:1).

Step 143.1: 8-(2-Fluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylicacid ethyl ester

SelectFluor (105 mg, 0.30 mmol) was added to a cold (−5° C.) solution of8-(3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid ethyl ester (Step115.1) (100 mg, 0.30 mmol) in CH₃CN (2 mL), under an argon atmosphere.The reaction mixture was allowed to warm to rt over 6 h and stirred atthat temperature for additional 12 h and diluted in EtOAc and asaturated aqueous solution of NaHCO₃. The aqueous phase was separatedand extracted with EtOAc. The combined organic layers were washed withH₂O and brine, dried (Na₂SO₄), filtered and concentrated. The residuewas purified by silica gel column chromatography (Hex/EtOAc, 3:2) toprovide 50 mg of the title compound as an off-white solid. Titlecompound: ESI-MS: 357.2 [M+H]⁺; t_(R)=4.58 min (System 1); TLC:R_(f)=0.24 (Hex/EtOAc, 3:2).

Example 1448-(2-Chloro-6-fluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid[5-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-yl]-amide

The title compound was prepared in analogy to the procedure described inExample 115 but using8-(2-chloro-6-fluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acidethyl ester (Step 144.1),5-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-ylamine (Example 31;purified by silica gel column chromatography), 2 equiv of trimethylaluminum, stirring the reaction mixture for 4 h at 80° C., pouring itonto a saturated aqueous solution of NaHCO₃ and DCM. Title compound:ESI-MS: 551.1 [M+H]⁺; t_(R)=3.50 min (System 1); TLC: R_(f)=0.20(DCM/MeOH/NH₃ ^(aq), 94:5:1).

Step 144.1:8-(2-Chloro-6-fluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acidethyl ester

Sulfuryl chloride (0.35 mL, 4.33 mmol, 1.1 equiv) in CH₃CN (10 mL) wasadded dropwise to a cold (−30° C.) solution of8-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acidethyl ester (Step 143.1) (1.4 g, 3.93 mmol) in CH₃CN (40 mL). Thereaction mixture was quenched by addition of a saturated solution ofNaHCO₃, allowed to warm to rt and concentrated. The residue was dilutedin EtOAc and a saturated solution of NaHCO₃. The aqueous phase wasseparated and extracted with EtOAc. The combined organic layers werewashed with H₂O and brine, dried (Na₂SO₄), filtered and concentrated.The residue was purified by silica gel column chromatography (Hex/EtOAc,3:2) to provide 1.27 g of the title compound as a white solid. Titlecompound: ESI-MS: 391.1 [M+H]⁺; t_(R)=4.71 min (System 1); TLC:R_(f)=0.12 (Hex/EtOAc, 3:2).

Example 1458-(2-Chloro-6-fluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid[5-(4-ethyl-piperazin-1-ylmethyl)-pyridin-2-yl]-amide

The title compound was prepared in analogy to the procedure described inExample 115 but using8-(2-chloro-6-fluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acidethyl ester (Step 144.1),5-(4-ethyl-piperazin-1-ylmethyl)-pyridin-2-ylamine (Example 26.1;purified by silica gel column chromatography), 2 equiv of trimethylaluminum, stirring the reaction mixture for 7 h at 80° C., pouring itonto a saturated aqueous solution of NaHCO₃ and DCM. Title compound:ESI-MS: 564.8 [M+H]⁺; t_(R)=3.57 min (System 1); TLC: R_(f)=0.25(DCM/MeOH/NH₃ ^(aq), 94:5:1).

Example 1468-(2-Chloro-6-fluoro-3,5-dimethoxy-Phenyl)-quinoxaline-5-carboxylic acid(5-piperazin-1-ylmethyl-pyridin-2-yl)-amide

Intermediate 146 was prepared in analogy to the procedure described inExample 115 but using8-(2-chloro-6-fluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acidethyl ester (Step 144.1),5-[4-(4-methoxy-benzyl)piperazin-1-ylmethyl]-pyridin-2-ylamine (Step105.1), 2 equiv of trimethyl aluminum, stirring the reaction mixture for4 h at 80° C., pouring it onto a saturated aqueous solution of NaHCO₃and DCM: ESI-MS: 657.0 [M+H]⁺; TLC: R_(f)=0.58 (DCM/MeOH/NH₃ ^(aq),94:5:1).

The title compound was prepared in analogy to the procedure described inExample 105 but stirring the reaction mixture for 0.5 h at 120° C.:ESI-MS: 537.0 [M+H]⁺; t_(R)=3.38 min (System 1); TLC: R_(f)=0.05(DCM/MeOH/NH₃ ^(aq), 91.5:7.5:1).

Example 1478-(2-Chloro-6-fluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid[5-(3-oxo-piperazin-1-ylmethyl)-pyridin-2-yl]-amide

The title compound was prepared in analogy to the procedure described inExample 115 but using8-(2-chloro-6-fluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acidethyl ester (Step 144.1), 4-(6-amino-pyridin-3-ylmethyl)-piperazin-2-one(Step 103.1), 2 equiv of trimethyl aluminum, stirring the reactionmixture for 6 h at 80° C., pouring it onto a saturated aqueous solutionof NaHCO₃ and DCM. The title compound: ESI-MS: 551.0 [M+H]⁺; t_(R)=3.59min (System 1); TLC: R_(f)=0.13 (DCM/MeOH/NH₃ ^(aq), 94:5:1).

Example 1488-(2-Chloro-6-fluoro-3,5-dimethoxy-Phenyl)-quinoxaline-5-carboxylic acid(5-{[(2-dimethylamino-ethyl)-methyl-amino]-methyl}-pyridin-2-yl)-amide

The title compound was prepared in analogy to the procedure described inExample 115 but using8-(2-chloro-6-fluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acidethyl ester (Step 144.1),N-(6-amino-pyridin-3-ylmethyl)-N,N′,N′-trimethyl-ethane-1,2-diamine(prepared as described in Example 26 but usingN,N,N′-trimethyl-ethane-1,2-diamine in Step 26.2 and purified by columnchromatography), 2 equiv of trimethyl aluminum, stirring the reactionmixture for 5 h at 80° C., pouring it onto a saturated aqueous solutionof NaHCO₃ and DCM. The title compound: ESI-MS: 553.1 [M+H]⁺; t_(R)=3.43min (System 1); TLC: R_(f)=0.06 (DCM/MeOH/NH₃ ^(aq), 94:5:1).

Example 1498-(2-Chloro-6-fluoro-3,5-dimethoxy-Phenyl)-quinoxaline-5-carboxylic acid{5-[(dimethylcarbamoylmethyl-methyl-amino)-methyl]-pyridin-2-yl}-amide

The title compound was prepared in analogy to the procedure described inStep 14.1 but using8-(2-chloro-6-fluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acidethyl ester (Step 144.1),2-[(6-amino-pyridin-3-ylmethyl)-methyl-amino]-N,N-dimethyl-acetamide(Step 119.1), stirring the reaction mixture for 72 h at rt. The titlecompound: ESI-MS: 583.0 [M+H]⁺; t_(R)=4.02 min (System 1); TLC:R_(f)=0.36 (DCM/MeOH, 9:1).

Example 1508-(2-Chloro-6-fluoro-3,5-dimethoxy-Phenyl)-quinoxaline-5-carboxylic acid{5-[(carbamoylmethyl-methyl-amino)-methyl]-pyridin-2-yl}-amide

The title compound was prepared in analogy to the procedure described inExample 115 but using8-(2-chloro-6-fluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acidethyl ester (Step 144.1),2-[(6-amino-pyridin-3-ylmethyl)-methyl-amino]-acetamide (Step 118.1), 2equiv of trimethyl aluminum, stirring the reaction mixture for 6 h at80° C. and pouring it onto a saturated aqueous solution of NaHCO₃ andDCM. The title compound: ESI-MS: 539.0 [M+H]⁺; t_(R)=3.61 min (System1); TLC: R_(f)=0.49 (DCM/MeOH/NH₃ ^(aq), 9:1).

Example 1518-(2-Chloro-6-fluoro-3,5-dimethoxy-Phenyl)-quinoxaline-5-carboxylic acid(5-imidazol-1-ylmethyl-pyridin-2-yl)-amide

The title compound was prepared in analogy to the procedure described inExample 115 but using8-(2-chloro-6-fluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acidethyl ester (Step 144.1), 5-imidazol-1-ylmethyl-pyridin-2-ylamine (Step120.1), 2 equiv of trimethyl aluminum, stirring the reaction mixture for3 h at 80° C. and pouring it onto a saturated aqueous solution of NaHCO₃and DCM. The title compound: ESI-MS: 519.0 [M+H]⁺; t_(R)=3.86 min(System 1); TLC: R_(f)=0.40 (DCM/MeOH, 9:1).

Example 1528-(2-Chloro-6-fluoro-3,5-dimethoxy-Phenyl)-quinoxaline-5-carboxylic acid[5-(1,1-dioxo-thiomorpholin-4-ylmethyl)-pyridin-2-yl]-amide

The title compound was prepared in analogy to the procedure described inExample 115 but using8-(2-chloro-6-fluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acidethyl ester (Step 144.1),5-(1,1-dioxothiomorpholin-4-ylmethyl)-pyridin-2-ylamine (Step 104.1), 2equiv of trimethyl aluminum, stirring the reaction mixture for 6 h at80° C., pouring it onto a saturated aqueous solution of NaHCO₃ and DCM.Title compound: ESI-MS: 585.9 [M+H]⁺; t_(R)=3.96 min (System 1); TLC:R_(f)=0.39 (DCM/MeOH/NH₃ ^(aq), 94:5:1).

Example 1538-(2-Chloro-6-fluoro-3,5-dimethoxy-Phenyl)-quinoxaline-5-carboxylic acid(4-dimethylaminomethyl-1H-imidazol-2-yl)-amide

The title compound was prepared in analogy to the procedures describedin Example 14 but using8-(2-chloro-6-fluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acidethyl ester (Step 144.1), Raney nickel and MeOH/THF (1:1) instead ofpalladium on carbon and MeOH in Step 14.2, anddimethyl-(2-nitro-1H-imidazol-4-ylmethyl)-amine (Step 22.1) instead of2-nitroimidazole in Step 14.3. The title compound: ESI-MS: 485.1 [M+H]⁺;t_(R)=3.24 min (System 1); TLC: R_(f)=0.20 (DCM/MeOH/NH₃ ^(aq),91.5:7.5:1).

Example 1548-(2-Chloro-6-fluoro-3,5-dimethoxy-Phenyl)-quinoxaline-5-carboxylic acid[4-(4-methyl-piperazin-1-ylmethyl)-1H-imidazol-2-yl]-amide

The title compound was prepared in analogy to the procedures describedin Example 14 but using8-(2-chloro-6-fluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acidethyl ester (Step 144.1), Raney nickel and MeOH/THF (1:1) instead ofpalladium on carbon and MeOH in Step 14.2, and1-methyl-4-(2-nitro-1H-imidazol-4-ylmethyl)-piperazine (Step 20.1)instead of 2-nitroimidazole in Step 14.3. Title compound: ESI-MS: 540.0[M+H]⁺; t_(R)=3.07 min (System 1); TLC: R_(f)=0.23 (DCM/MeOH/NH₃ ^(aq),94:5:1).

Example 1558-(2-Chloro-6-fluoro-3,5-dimethoxy-Phenyl)-quinoxaline-5-carboxylic acid[4-(3-oxo-piperazin-1-ylmethyl)-1H-imidazol-2-yl]-amide

The title compound was prepared in analogy to the procedures describedin Example 14 but using8-(2-chloro-6-fluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acidethyl ester (Step 144.1), Raney nickel and MeOH/THF (1:1) instead ofpalladium on carbon and MeOH in Step 14.2, and4-(2-nitro-1H-imidazol-4-ylmethyl)-piperazin-2-one (Step 142.1) insteadof 2-nitroimidazole in Step 14.3. Title compound: ESI-MS: 540.0 [M+H]⁺;t_(R)=3.18 min (System 1); TLC: R_(f)=0.18 (DCM/MeOH, 9:1).

Example 1568-(2,6-Dichloro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid[5-(4-benzyl-piperazin-1-ylmethyl)-pyridin-2-yl]-amide

The title compound was prepared in analogy to the procedure described inStep 14.1 but using 5-(4-benzyl-piperazin-1-ylmethyl)-pyridin-2-ylamine(Step 156.1) and stirring the reaction mixture for 72 h at rt. Titlecompound: ESI-MS: 643.0 [M+H]⁺; t_(R)=4.02 min (System 1); TLC:R_(f)=0.55 (DCM/MeOH, 9:1).

Step 156.1: 5-(4-Benzyl-piperazin-1-ylmethyl)-pyridin-2-ylamine

The title compound was prepared in analogy to the procedures describedin Steps 100.1-100.2 but using 1-benzyl-piperazine in Step 100.2:ESI-MS: 283.2 [M+H]⁺.

Example 1578-(2,6-Difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid{4-[(ethyl-methyl-amino)-methyl]-1H-imidazol-2-yl}-amide

The title compound was prepared in analogy to the procedures describedin Example 14 but using8-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acidethyl ester (Step 124.1) and stirring the reaction mixture for 3 h at70° C. Ethyl-methyl-(2-nitro-1H-imidazol-4-ylmethyl)-amine (Step 157.1)instead of 2-nitroimidazole was used in Step 14.3, and Raney nickel andMeOH/THF (1:1) instead of palladium on carbon and MeOH in Step 14.2.Title compound: ESI-MS: 483.9 [M+H]⁺; TLC: R_(f)=0.10 (DCM/MeOH, 9:1).

Step 157.1: Ethyl-methyl-(2-nitro-1H-imidazol-4-ylmethyl)-amine

The title compound was prepared in analogy to the procedure described inStep 18.1 but using 2 equivalents of 2-nitroimidazole,ethyl-methyl-amine instead of diethyl amine, and stirring the reactionmixture for 72 h at 82° C. The residue was purified by silica gel columnchromatography (DCM/MeOH/NH₃ ^(aq), 89:10:1, then 84:15:1) to afford animpure sample of the title compound which was used without furtherpurification.

Example 1588-(2,6-Difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid(4-diethylaminomethyl-1H-imidazol-2-yl)-amide

The title compound was prepared in analogy to the procedures describedin Example 14 but stirring the reaction mixture at 70° C. for 7 h andusing 8-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylicacid ethyl ester (Step 124.1).Diethyl-(2-nitro-1H-imidazol-4-ylmethyl)-amine (Step 18.1) instead of2-nitroimidazole was used in Step 14.3, and Raney nickel and MeOH/THF(1:1) instead of palladium on carbon and MeOH in Step 14.2. Titlecompound: ESI-MS: 497.0 [M+H]⁺; t_(R)=3.36 min (System 1); TLC:R_(f)=0.18 (DCM/MeOH/NH₃ ^(aq), 91.5:7.5:1).

Example 159 5-(2,6-Dichloro-3,5-dimethoxy-phenyl)-quinoline-8-carboxylicacid [4-(4-ethyl-piperazin-1-yl)-phenyl]-amide

A mixture of propylphosphonic anhydride (50% in DMF, 0.41 mL, 0.70 mmol,2 equiv), 5-(2,6-dichloro-3,5-dimethoxy-phenyl)-quinoline-8-carboxylicacid (Step 159.1) (132 mg, 0.35 mmol), 4-(4-ethylpiperazin-1-yl)-aniline(Step 1.9) (79 mg, 0.39 mmol, 1.1 equiv), DMAP (3 mg), and Et₃N (0.49mL, 3.5 mmol, 10 equiv) in DMF (3 mL), was stirred for 16 h at rt, underan argon atmosphere. The reaction mixture was diluted with EtOAc andH₂O. The aqueous layer was separated and extracted with EtOAc. Thecombined organic phase was washed with brine, dried (Na₂SO₄), filteredand concentrated. The residue was purified by trituration in EtOAc toafford the title compound as a yellow solid: ES-MS: 564.9/566.9 [M+H]⁺;t_(R)=4.45 min (System 1).

Step 159.1: 5-(2,6-Dichloro-3,5-dimethoxy-phenyl)-quinoline-8-carboxylicacid

Sulfuryl chloride (0.1 mL, 1.19 mmol, 1.5 equiv) was added dropwise to acold (5° C.) suspension of5-(3,5-dimethoxy-phenyl)-quinoline-8-carboxylic acid (Step 159.2) (245mg, 0.79 mmol) in CH₃CN (5 mL). The reaction mixture was stirred at 5°C. for 15 min, quenched by addition of H₂O (0.2 mL), and concentrated.Trituration of the residue in H₂O provided 270 mg of the title compoundas a white solid: ESI-MS: 378.0/380.0 [M+H]⁺; t_(R)=4.48 min (System 1).

Step 159.2: 5-(3,5-Dimethoxy-phenyl)-quinoline-8-carboxylic acid

A mixture of 3,5-dimethoxyphenylboronic acid (217 mg, 1.19 mmol, 1.2equiv) (Step 1.8) in EtOH (0.5 mL) was added dropwise to a mixture of5-bromo-quinoline-8-carboxylic acid (Step 159.3) (250 mg, 0.99 mmol),PdCl₂(dppf) (22 mg, 0.03 mmol, 0.03 equiv), Na₂CO₃ (2M solution in H₂O,1 mL, 3.97 mmol, 4 equiv) in toluene (5 mL) at 105° C., under an argonatmosphere. The reaction mixture was stirred at 105° C. for 1 h, allowedto cool to rt, diluted with EtOAc and H₂O, basified by addition of a 2Naqueous solution of NaOH (2 mL), filtered through a pad of celite andthe filtrate was extracted with EtOAc. The aqueous layer was separatedand acidified to pH 5. The resulting precipitate was collected by vacuumfiltration to provide 248 mg of the title compound as a white solid:ESI-MS: 310.1 [M+H]⁺; t_(R)=4.06 min (System 1).

Step 159.3: 5-Bromo-quinoline-8-carboxylic acid

A solution of potassium permanganate (18.2 g, 115.5 mmol, 2 equiv) inH₂O (200 mL) was added to a hot (110° C.) solution of5-bromo-8-methyl-quinoline (Step 159.4) (12.8 g, 57.7 mmol) in pyridine(120 mL). The reaction mixture was stirred for 10 min at 110° C. andfiltered while hot. The residue in the filter was washed with H₂O andpyridine. The filtrate was concentrated to remove pyridine, diluted withEt₂O and basified by addition of a 2 N aqueous solution of NaOH (20 mL).The aqueous layer was separated and made acidic (pH 3) by addition of a2 N aqueous solution of HCl. The resulting precipitate was collected byvacuum filtration to provide 1.45 g of the title compound as a greensolid: ESI-MS: 251.9/253.9 [M+H]⁺; t_(R)=3.56 min (System 1).

Step 159.4: 5-Bromo-8-methyl-quinoline

NBS (13.7 g, 76.9 mmol, 1.1 equiv) was added portionwise to a cold (5°C.) solution of 8-methyl-quinoline (10 g, 69.9 mmol) in concentratedH₂SO₄ (150 mL). The reaction mixture was stirred for 18 h at 5° C.,diluted in ice (300 mL) and basified by addition of an aqueous solutionof NaOH (10% wt). The resulting white solid was collected by vacuumfiltration, rinsed with water, and dissolved in DCM. The organic phasewas washed with H₂O and brine, dried (Na₂SO₄), filtered and concentratedto afford 15.2 g of the title compound as a beige solid: ESI-MS:221.9/223.9 [M+H]⁺; t_(R)=3.59 min (System 1).

Example 160 5-(2,6-Dichloro-3,5-dimethoxy-phenyl)-quinoline-8-carboxylicacid (1-benzyl-1H-imidazol-2-yl)-amide

The title compound was prepared in analogy to the procedure described inExample 159 but using 1-benzyl-1H-imidazol-2-ylamine (Step 160.1). Thetitle compound: ESI-MS: 532.9 [M+H]⁺; t_(R)=4.75 min (System 1).

Step 160.1: 1-Benzyl-1H-imidazol-2-ylamine

A suspension of 1-benzyl-2-nitro-1H-imidazole (Step 160.2) (410 mg, 1.16mmol) and Raney nickel (40 mg) in MeOH (10 mL) was stirred for 3 h atrt, under a hydrogen atmosphere. The reaction mixture was filteredthrough a pad of celite and concentrated to afford 345 mg of the titlecompound as a brown solid: ESI-MS: 173.9 [M+H]⁺; t_(R)=2.02 min (System1).

Step 160.2: 1-Benzyl-2-nitro-1H-imidazole

Benzyl chloride (1.8 mL, 15.4 mmol, 1.2 equiv) was added to a solutionof 2-nitroimidazole (1.45 g, 12.8 mmol) and triethylamine (3.6 mL, 25.7mmol, 2 equiv) in DCM (40 mL). The reaction mixture was stirred atreflux for 72 h, allowed to cool to rt, diluted with DCM, washed withH₂O and brine, dried (sodium sulfate), filtered and concentrated. Theresidue was purified by silica gel column chromatography (Hex/EtOAc,7:3) to afford 1.31 g of the title compound as a white solid: ES-MS:204.0 [M+H]⁺; t_(R)=3.72 min (System 1); TLC: R_(f)=0.22 (Hex/EtOAc,7:3).

Example 161 5-(2,6-Dichloro-3,5-dimethoxy-phenyl)-quinoline-8-carboxylicacid (1H-imidazol-2-yl)-amide

A suspension of5-(2,6-dichloro-3,5-dimethoxy-phenyl)-quinoline-8-carboxylic acid(1-benzyl-1H-imidazol-2-yl)-amide (Example 160) (100 mg, 1.16 mmol) andpalladium hydroxyde (75 mg) in MeOH (5 mL) was stirred for 72 h at rt,under a hydrogen atmosphere. The reaction mixture was filtered through apad of celite and concentrated. The residue was purified by silica gelcolumn chromatography (Hex/EtOAc, 1:4) followed by trituration in Et₂Oto provide 15 mg of the title compound as a yellow solid: ES-MS: 442.9[M+H]⁺; t_(R)=4.05 min (System 1); TLC: R_(f)=0.08 (Hex/EtOAc, 1:4).

Example 162 5-(2,6-Dichloro-3,5-dimethoxy-phenyl)-quinoline-8-carboxylicacid (3H-imidazol-4-yl)-amide

The title compound was prepared in analogy to the procedures describedin Example 14 but using5-(2,6-dichloro-3,5-dimethoxy-phenyl)-quinoline-8-carboxylic acid (Step159.1), stirring the reaction mixture for 3 h at 70° C., and using4-nitro-imidazole instead of 2-nitroimidazole in Step 14.3. The titlecompound: ESI-MS: 442.9 [M+H]⁺; t_(R)=3.93 min (System 1); TLC:R_(f)=0.17 (DCM/MeOH/NH₃ ^(aq), 94:5:1).

Example 1638-(2,6-Dichloro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid(4H-[1,2,4]triazol-3-yl)-amide

The title compound was prepared in analogy to the procedures describedin Example 14 but using5-(2,6-dichloro-3,5-dimethoxy-phenyl)-quinoline-8-carboxylic acid (Step159.1), stirring the reaction mixture for 4 h at 70° C., and using3-nitro-1,2,4-triazole instead of 2-nitroimidazole in Step 14.3. Thetitle compound: ESI-MS: 443.9 [M+H]⁺; t_(R)=4.60 min (System 1); TLC:R_(f)=0.33 (DCM/MeOH/NH₃ ^(aq), 94:5:1).

Example 164 5-(2,6-Dichloro-3,5-dimethoxy-phenyl)-Quinoline-8-carboxylicacid [5-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-yl]-amide

The title compound was prepared in analogy to the procedure described inStep 14.1 but using5-(2,6-dichloro-3,5-dimethoxy-phenyl)-quinoline-8-carboxylic acid (Step159.1), 5-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-ylamine (Example 31;purified by silica gel column chromatography), and stirring the reactionmixture for 20 h at rt. Title compound: ESI-MS: 566.1 [M+H]⁺; TLC:R_(f)=0.22 (DCM/MeOH, 9:1).

Example 165 5-(2,6-Dichloro-3,5-dimethoxy-phenyl)-quinoline-8-carboxylicacid [5-(4-ethyl-piperazin-1-ylmethyl)-pyridin-2-yl]-amide

The title compound was prepared in analogy to the procedure described inStep 14.1 but using5-(2,6-dichloro-3,5-dimethoxy-phenyl)-quinoline-8-carboxylic acid (Step159.1), 5-(4-ethyl-piperazin-1-ylmethyl)-pyridin-2-ylamine (Step 26.1;purified by silica gel column chromatography), and stirring the reactionmixture for 20 h at rt. Title compound: ESI-MS: 580.1 [M+H]⁺; t_(R)=3.80min (System 1); TLC: R_(f)=0.27 (DCM/MeOH/NH₃ ^(aq), 94:5:1).

Example 166 5-(2,6-Dichloro-3,5-dimethoxy-phenyl)-quinoline-8-carboxylicacid {5-[4-(4-methoxy-benzyl)-piperazin-1-ylmethyl]-pyridin-2-yl}-amide

The title compound was prepared in analogy to the procedure described inStep 14.1 but using5-(2,6-dichloro-3,5-dimethoxy-phenyl)-quinoline-8-carboxylic acid (Step159.1), 5-[4-(4-methoxy-benzyl)-piperazin-1-ylmethyl]-pyridin-2-ylamine(Step 105.1) and stirring the reaction mixture for 20 h at rt. Titlecompound: ESI-MS: 672.0 [M+H]⁺; TLC: R_(f)=0.25 (DCM/MeOH, 9:1).

Example 167 5-(2,6-Dichloro-3,5-dimethoxy-phenyl)-quinoline-8-carboxylicacid (5-piperazin-1-ylmethyl-pyridin-2-yl)-amide

The title compound was prepared in analogy to the procedure described inExample 105 but using5-(2,6-dichloro-3,5-dimethoxy-phenyl)-quinoline-8-carboxylic acid{5-[4-(4-methoxy-benzyl)-piperazin-1-ylmethyl]-pyridin-2-yl}-amide(Example 166) and stirring the reaction mixture for 1 h at 120° C. Titlecompound: ESI-MS: 552.1 [M+H]⁺; TLC: R_(f)=0.12 (DCM/MeOH, 9:1).

Example 168 5-(2,6-Dichloro-3,5-dimethoxy-Phenyl)-quinoline-8-carboxylicacid [6-(4-methyl-piperazin-1-ylmethyl)-pyridin-3-yl]-amide

The title compound was prepared in analogy to the procedure described inStep 14.1 but using5-(2,6-dichloro-3,5-dimethoxy-phenyl)-quinoline-8-carboxylic acid (Step159.1), 6-(4-methyl-piperazin-1-ylmethyl)-pyridin-3-ylamine (Step 39.1),and stirring the reaction mixture for 3 h at rt. Title compound: ESI-MS:566.0 [M+H]⁺; t_(R)=3.64 min (System 1); TLC: R_(f)=0.24 (DCM/MeOH,9:1).

Example 169 5-(2,6-Dichloro-3,5-dimethoxy-phenyl)-quinoline-8-carboxylicacid [6-(4-ethyl-piperazin-1-ylmethyl)-pyridin-3-yl]-amide

The title compound was prepared in analogy to the procedure described inStep 14.1 but using5-(2,6-dichloro-3,5-dimethoxy-phenyl)-quinoline-8-carboxylic acid (Step159.1), 6-(4-ethyl-piperazin-1-ylmethyl)-pyridin-3-ylamine (prepared asdescribed in Example 39 but using N-ethyl-piperazine in Step 39.2), andstirring the reaction mixture for 3 h at rt. Title compound: ESI-MS:580.1 [M+H]⁺; t_(R)=3.70 min (System 1); TLC: R_(f)=0.33 (DCM/MeOH,9:1).

Example 170 5-(2,6-Dichloro-3,5-dimethoxy-phenyl)-quinoline-8-carboxylicacid {6-[4-(4-methoxy-benzyl)-piperazin-1-ylmethyl]-pyridin-3-yl}-amide

The title compound was prepared in analogy to the procedure described inStep 14.1 but using5-(2,6-dichloro-3,5-dimethoxy-phenyl)-quinoline-8-carboxylic acid (Step159.1), 6-[4-(4-methoxy-benzyl)-piperazin-1-ylmethyl]-pyridin-3-ylamine(Step 111.1) and stirring the reaction mixture for 20 h at rt. Titlecompound: ESI-MS: 672.1 [M+H]⁺; TLC: R_(f)=0.45 (DCM/MeOH, 9:1).

Example 171 5-(2,6-Dichloro-3,5-dimethoxy-phenyl)-quinoline-8-carboxylicacid (6-piperazin-1-ylmethyl-pyridin-3-yl)-amide

The title compound was prepared in analogy to the procedure described inExample 105 but using5-(2,6-dichloro-3,5-dimethoxy-phenyl)-quinoline-8-carboxylic acid(6-piperazin-1-ylmethyl-pyridin-3-yl)-amide (Example 170) and stirringthe reaction mixture for 1 h at 120° C. Title compound: ESI-MS: 552.0[M+H]⁺; t_(R)=3.57 min (System 1); TLC: R_(f)=0.12 (DCM/MeOH, 9:1).

Example 172 5-(2,6-Dichloro-3,5-dimethoxy-phenyl)-quinoline-8-carboxylicacid (4-dimethylaminomethyl-1H-imidazol-2-yl)-amide

The title compound was prepared in analogy to the procedures describedin Example 14 but using5-(2,6-dichloro-3,5-dimethoxy-phenyl)-quinoline-8-carboxylic acid(6-piperazin-1-ylmethyl-pyridin-3-yl)-amide (Example 170),dimethyl-(2-nitro-1H-imidazol-4-ylmethyl)-amine (Step 22.1) instead of2-nitroimidazole in Step 14.3, and Raney nickel and MeOH/THF (1:1)instead of palladium on carbon and MeOH in Step 14.2. The titlecompound: ESI-MS: 500.0 [M+H]⁺; t_(R)=3.50 min (System 1); TLC:R_(f)=0.20 (DCM/MeOH, 9:1).

Example 173 5-(2,6-Dichloro-3,5-dimethoxy-phenyl)-quinoline-8-carboxylicacid(5-{[(2-dimethylamino-ethyl)-methyl-amino]-methyl}-pyridin-2-yl)-amide

The title compound was prepared in analogy to the procedure described inStep 14.1 but using5-(2,6-dichloro-3,5-dimethoxy-phenyl)-quinoline-8-carboxylic acid(6-piperazin-1-ylmethyl-pyridin-3-yl)-amide (Example 170),N-(6-amino-pyridin-3-ylmethyl)-N,N′,N′-trimethyl-ethane-1,2-diamine(prepared as described in Example 26 but usingN,N,N′-trimethyl-ethane-1,2-diamine in Step 26.2), and stirring thereaction mixture for 14 h at rt. Title compound: ESI-MS: 568.0 [M+H]⁺;TLC: R_(f)=0.15 (DCM/MeOH, 9:1).

Example 174 5-(2,6-Difluoro-3,5-dimethoxy-phenyl)-quinoline-8-carboxylicacid [5-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-yl]-amide

The title compound was prepared in analogy to the procedure described inExample 115 but using5-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoline-8-carboxylic acid ethylester (Step 174.1), 5-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-ylamine(Example 31; purified by silica gel column chromatography), 2 equiv oftrimethyl aluminum, stirring the reaction mixture for 2 h at 80° C.Title compound: ESI-MS: 534.1 [M+H]⁺; t_(R)=3.56 min (System 1); TLC:R_(f)=0.14 (DCM/MeOH/NH₃ ^(aq), 94:5:1).

Step 174.1: 5-(2,6-Difluoro-3,5-dimethoxy-phenyl)-quinoline-8-carboxylicacid ethyl ester

SelectFluor (2.04 g, 5.8 mmol, 2 equiv) was added to a cold (−5° C.)solution of 5-(3,5-dimethoxy-phenyl)-quinoline-8-carboxylic acid ethylester (Step 174.2) (970 mg, 2.9 mmol) in CH₃CN (40 mL), under an argonatmosphere. The reaction mixture was allowed to warm to rt, stirred atthat temperature for 6 h, quenched by addition of a saturated aqueoussolution of NaHCO₃, and concentrated. The residue was diluted in EtOAcand a saturated aqueous solution of NaHCO₃. The aqueous phase wasseparated and extracted with EtOAc. The combined organic layers werewashed with H₂O and brine, dried (Na₂SO₄), filtered and concentrated.The residue was purified by silica gel column chromatography (Hex/EtOAc,3:2) followed by trituration in Et₂O to provide 257 mg of the titlecompound: ESI-MS: 374.0 [M+H]⁺; t_(R)=3.81 min (System 1); TLC:R_(f)=0.13 (Hex/EtOAc, 3:2).

Step 174.2: 5-(3,5-Dimethoxy-phenyl)-quinoline-8-carboxylic acid ethylester

A mixture of 5-(3,5-dimethoxy-phenyl)-quinoline-8-carboxylic acid (Step159.2) (2 g), H₂SO₄ conc. (0.6 mL) and EtOH (100 mL) was stirred atreflux for 30 h, allowed to cool and concentrated. The residue wasdiluted in EtOAc and a saturated aqueous solution of NaHCO₃. The aqueousphase was separated and extracted with EtOAc. The combined organiclayers were washed with H₂O and brine, dried (Na₂SO₄), filtered andconcentrated. The residue was purified by silica gel columnchromatography (Hex/EtOAc, 3:2) to provide 1.77 g of the title compoundas a white solid. Title compound: ESI-MS: 338.2 [M+H]⁺; t_(R)=3.81 min(System 1); TLC: R_(f)=0.29 (Hex/EtOAc, 3:2).

Example 175 5-(2,6-Difluoro-3,5-dimethoxy-phenyl)-quinoline-8-carboxylicacid (4-dimethylaminomethyl-1H-imidazol-2-yl)-amide

The title compound was prepared in analogy to the procedures describedin Example 14 but using8-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acidethyl ester (Step 124.1), stirring the reaction mixture for 7 h at 70°C., and using dimethyl-(2-nitro-1H-imidazol-4-ylmethyl)-amine (Step22.1) instead of 2-nitroimidazole in Step 14.3, and Raney nickel andMeOH/THF (1:1) instead of palladium on carbon and MeOH in Step 14.2. Thetitle compound: ESI-MS: 468.1 [M+H]⁺; t_(R)=3.29 min (System 1); TLC:R_(f)=0.18 (DCM/MeOH/NH₃ ^(aq), 91.5:7.5:1).

Example 1765-(2-Chloro-6-fluoro-3,5-dimethoxy-phenyl)-quinoline-8-carboxylic acid[5-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-yl]-amide

The title compound was prepared in analogy to the procedure described inStep 14.1 but using5-(2-chloro-6-fluoro-3,5-dimethoxy-phenyl)-quinoline-8-carboxylic (Step176.1), 5-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-ylamine (Example 31;purified by silica gel column chromatography), and stirring the reactionmixture for 16 h at rt. Title compound: ESI-MS: 550.1 [M+H]⁺; TLC:R_(f)=0.20 (DCM/MeOH/NH₃ ^(aq), 94:5:1).

Step 176.1:5-(2-Chloro-6-fluoro-3,5-dimethoxy-phenyl)-quinoline-8-carboxylic acid

A mixture of5-(2-chloro-6-fluoro-3,5-dimethoxy-phenyl)-quinoline-8-carboxylic acidethyl ester (Step 176.2) (235 mg, 0.60 mmol), a 2 N aqueous solution ofLiOH (3 mL) and THF (3 mL) was stirred for 20 h at rt, diluted with H₂Oand extracted with Et₂O. The aqueous layer was acidified to pH 4 byaddition of a 2 N aqueous solution of HCl. The resulting whiteprecipitate was collected by vacuum filtration providing 210 mg of thetitle compound: ESI-MS: 362.1 [M+H]⁺; t_(R)=4.24 min (System 1).

Step 176.2:5-(2-Chloro-6-fluoro-3,5-dimethoxy-phenyl)-quinoline-8-carboxylicacidethyl ester

Sulfuryl chloride (75 μL, 0.93 mmol) was added dropwise to a cold (−20°C.) solution of 5-(2-fluoro-3,5-dimethoxy-phenyl)-quinoline-8-carboxylicacid ethyl ester (Step 176.3) (330 mg, 0.93 mmol) in CH₃CN (6 mL). Thereaction mixture was stirred for 10 min at −20° C., quenched by additionof a saturated solution of NaHCO₃, and concentrated. The residue wasdiluted in EtOAc and a saturated solution of NaHCO₃. The aqueous phasewas separated and extracted with EtOAc. The combined organic layers werewashed with H₂O and brine, dried (Na₂SO₄), filtered and concentrated.The residue was purified by silica gel column chromatography (Hex/EtOAc,3:2) to provide 240 mg of the title compound as a white solid. Titlecompound: ESI-MS: 390.1 [M+H]⁺; t_(R)=3.98 min (System 1); TLC:R_(f)=0.15 (Hex/EtOAc, 3:2).

Step 176.3: 5-(2-Fluoro-3,5-dimethoxy-phenyl)-quinoline-8-carboxylicacid ethyl ester

SelectFluor (2.04 g, 5.8 mmol, 2 equiv) was added to a cold (−5° C.)solution of 5-(3,5-dimethoxy-phenyl)-quinoline-8-carboxylic acid ethylester (Step 174.2) (970 mg, 2.9 mmol) in CH₃CN (40 mL), under an argonatmosphere. The reaction mixture was allowed to warm to rt, stirred atthat temperature for 6 h, quenched by addition of a saturated aqueoussolution of NaHCO₃, and concentrated. The residue was diluted in EtOAcand a saturated aqueous solution of NaHCO₃. The aqueous phase wasseparated and extracted with EtOAc. The combined organic layers werewashed with H₂O and brine, dried (Na₂SO₄), filtered and concentrated.The residue was purified by silica gel column chromatography (Hex/EtOAc,3:2) followed by trituration in Et₂O to provide 355 mg of the titlecompound: ESI-MS: 356.2 [M+H]⁺; t_(R)=3.80 min (System 1); TLC:R_(f)=0.18 (Hex/EtOAc, 3:2).

Example 1775-(2-Chloro-6-fluoro-3,5-dimethoxy-Phenyl)-quinoline-8-carboxylic acid(4-dimethylaminomethyl-1H-imidazol-2-yl)-amide

The title compound was prepared in analogy to the procedures describedin Example 14 but using5-(2-chloro-6-fluoro-3,5-dimethoxy-phenyl)-quinoline-8-carboxylic (Step176.1), stirring the reaction mixture for 8 h at 70° C., and usingdimethyl-(2-nitro-1H-imidazol-4-ylmethyl)-amine (Step 22.1) instead of2-nitroimidazole in Step 14.3, and Raney nickel and MeOH/THF (1:1)instead of palladium on carbon and MeOH in Step 14.2. The titlecompound: ESI-MS: 484.1 [M+H]⁺; t_(R)=3.39 min (System 1); TLC:R_(f)=0.15 (DCM/MeOH/NH₃ ^(aq), 91.5:7.5:1).

Example 1785-(2-Chloro-6-fluoro-3,5-dimethoxy-phenyl)-quinoline-8-carboxylic acid[4-(4-methyl-piperazin-1-ylmethyl)-1H-imidazol-2-yl]-amide

The title compound was prepared in analogy to the procedures describedin Example 14 but using5-(2-chloro-6-fluoro-3,5-dimethoxy-phenyl)-quinoline-8-carboxylic (Step176.1), stirring the reaction mixture for 8 h at 70° C., and using1-methyl-4-(2-nitro-1H-imidazol-4-ylmethyl)-15 piperazine (Step 20.1)instead of 2-nitroimidazole in Step 14.3, and Raney nickel and MeOH/THF(1:1) instead of palladium on carbon and MeOH in Step 14.2. Titlecompound: ESI-MS: 539.1 [M+H]⁺; t_(R)=3.33 min (System 1); TLC:R_(f)=0.22 (DCM/MeOH/NH₃ ^(aq), 94:5:1).

Example 1798-(2,6-Dichloro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid(4-formyl-1H-imidazol-2-yl)-amide

A mixture of8-(2,6-dichloro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid (300mg, 0.791 mmol) (Step 179.1),2-amino-4-diethoxymethyl-imidazole-1-carboxylic acid tert-butyl ester(226 mg, 0.791 mmol) (Step 179.8), TBTU (305 mg, 0.949 mmol, 1.2 equiv)and DIEA (409 mg, 3.17 mmol, 4 equiv) in DMF (6 mL) was stirred for 48 hat rt. After further addition of2-amino-4-diethoxymethyl-imidazole-1-carboxylic acid tert-butyl ester(80 mg, 0.280 mmol) (Step 179.8), the reaction mixture was stirred foradditional 72 h at rt, diluted with EtOAc/H₂O and extracted with EtOAc.The organic phase was washed with H₂O and brine, dried (Na₂SO₄),filtered and concentrated. The residue was purified by silica gel columnchromatography (EtOAc/Hex, 1:1) to afford 470 mg of a mixture ofproducts. Part of this mixture (280 mg) was dissolved in acetone (3 mL)and H₂O (2 mL) and treated with PPTS (10.9 mg). The reaction mixture wasstirred for 7 h at rt, heated to 50° C., stirred for 20 h, allowed tocool to rt and diluted with EtOAc/H₂O. The resulting yellow precipitatewas collected by vacuum filtration and dried to provide 128 mg of thetitle compound: ES-MS: 472 [M+H]+; t_(R)=4.16 min (System 1).

Step 179.1:8-(2,6-Dichloro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid

Sulfuryl chloride (1.7 mL, 21.3 mmol, 2 equiv) was added dropwise to acold (5° C.) suspension of8-(3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid (Step 179.2) (3.3g, 10.6 mmol) in CH₃CN (30 mL). The reaction mixture was stirred at 5°C. for 2 h, quenched by addition of H₂O, and concentrated. Triturationof the residue in H₂O provided 4.0 g of the title compound as a whitesolid: ESI-MS: 379 [M+H]⁺; t_(R)=4.54 min (System 1).

Step 179.2: 8-(3,5-Dimethoxy-phenyl)-quinoxaline-5-carboxylic acid

KOH (6.0 g, 107 mmol, 10 equiv) was added to8-(3,5-dimethoxy-phenyl)-quinoxaline-5-carbonitrile (Step 179.3) (3.12g, 10.7 mmol) in ethylene glycol (30 mL). The reaction mixture wasstirred at 150° C. for 3 h (a solution was obtained), allowed to cool tort, diluted with Et₂O/H₂O, and extracted with Et₂O. The aqueous phasewas acidified to pH 5 by addition of HCl. Vacuum filtration of theresulting suspension afforded 3.3 g of the title compound as a yellowsolid: ESI-MS: 311 [M+H]⁺; t_(R)=4.34 min (System 1).

Step 179.3: 8-(3,5-Dimethoxy-phenyl)-quinoxaline-5-carbonitrile

A mixture of 5-bromo-8-(3,5-dimethoxy-phenyl)-quinoxaline (Step 179.4)(4.54 g, 13.2 mmol) and CuCN (1.54 g, 17.1 mmol, 1.3 equiv) in NMP (50mL) was stirred for 2 h at 180° C., under an argon atmosphere. Thereaction mixture was allowed to cool to rt, diluted with EtOAc/(10%aqueous solution of ethylenediamine) (150 mL), and filtered to afford1.19 g (batch 1) of the title compound as a yellow solid. The filtratewas extracted with DCM. The organic phase was washed with H₂O and brine,dried (Na₂SO₄), filtered and concentrated. The residue was triturated inEtOAc to provide 2.31 g (batch 2) of the title compound: ESI-MS: 292[M+H]⁺; t_(R)=4.53 min (System 1).

Step 179.4: 5-Bromo-8-(3,5-dimethoxy-phenyl)-quinoxaline

A mixture of 3,5-dimethoxyphenylboronic acid (3.38 g, 18.6 mmol) in EtOH(15 mL) was added dropwise to a mixture of 5,8-dibromo-quinoxaline (Step179.5) (10.7 g, 37.1 mmol, 2 equiv), PdCl₂(dppf) (530 mg, 0.7 mmol, 0.03equiv), Na₂CO₃ (2 M solution in H₂O, 37 mL, 74.3 mmol, 4 equiv) intoluene (100 mL) at 105° C., under an argon atmosphere. The reactionmixture was stirred at 105° C. for 2 h, allowed to cool to rt, dilutedwith EtOAc and H₂O, filtered through a pad of celite and extracted withEtOAc. The organic phase was washed with H₂O and brine, dried (Na₂SO₄),filtered and concentrated in vacuo. The crude product was purified bytrituration in DCM, followed by silica gel column chromatography(Hex/EtOAc, 4:1) to afford 4.54 g of the title compound as a yellowsolid: ES-MS: 345 [M+H]⁺; t_(R)=5.13 min (System 1); R_(f)=0.17(Hex/EtOAc, 4:1).

Step 179.5: 5,8-Dibromo-quinoxaline

A 40% aqueous solution of glyoxal (8.8 M, 6.3 mL, 55.1 mmol, 1.3 equiv)was added to a suspension of 3,6-dibromo-benzene-1,2-diamine (Step179.6) (11.3 g, 42.4 mmol) in EtOH (280 mL). The reaction mixture washeated to reflux for 3 h and allowed to cool to rt overnight. Vacuumfiltration of the reaction mixture afforded 9.7 g of the title compoundas a yellow solid: APCI-MS: 286/288/291 [M−1]⁻; t_(R)=4.40 min (System1).

Step 179.6: 3,6-Dibromo-benzene-1,2-diamine

NaBH₄ (26 g, 680 mmol, 10 equiv) was added portionwise (2 h) to avigorously stirred suspension of 4,7-dibromo-benzo[1,2,5]thiadiazole(Step 179.7) (20 g, 68.0 mmol) in EtOH (400 mL), under a nitrogenatmosphere and keeping the internal temperature below 15° C. Thereaction mixture was allowed to warm to 30° C., stirred for 1 h, cooledto 5° C., quenched by addition of H₂O (50 mL), and concentrated. Theresidue was diluted with Et₂O/H₂O. The resulting suspension was filteredand the filtrate extracted with Et₂O. The organic phase was washed withH₂O and brine, dried (Na₂SO₄), filtered and concentrated. The residuewas triturated in hexane to provide 12 g of the title compound as awhite solid: ESI-MS: 263/265/267 [M−H]⁻; t_(R)=4.20 min (System 1).

Step 179.7: 4,7-Dibromo-benzo[1,2,5]thiadiazole

Bromine (18.6 mL, 265 mmol, 1.2 equiv) was added to a refluxing solutionof 1,2,5-benzothiazole (30 g, 220 mmol) in HBr (48% in H₂O, 150 mL). Thereaction mixture was stirred for 4 h at reflux and allowed to cool tort. The resulting solid was collected by vacuum filtration, washed withH₂O, dried under vacuum, and triturated in MeOH to afford 63 g of thetitle compound as an off-white solid: ¹H NMR (400 MHz, DMSO-d6) δ(ppm):8.00 (s, 2H); t_(R)=5.05 min (System 1).

Step 179.8: 2-Amino-4-diethoxymethyl-imidazole-1-carboxylic acidtert-butyl ester

A mixture of 3-bromo-1,1-diethoxy-propan-2-one (21.3 g, 95 mmol) (Step179.9) and N-tert-butoxycarbonylguanidine (45.3 g, 284 mmol, 3 equiv)(Step 179.10) was stirred at 50° C. for 8 h. The reaction mixture wasconcentrated, diluted in EtOAc/H₂O and extracted with EtOAc. The organicphase was washed with water and brine, dried (Na₂SO₄) and concentrated.The residue was purified by silica gel column chromatography (DCM/EtOAc,3:7) followed by trituration in Et₂O to afford 11.3 g of the titlecompound as a white solid: ES-MS: 286 [M+H]⁺; R_(f)=0.34 (DCM/EtOAc,3:7).

Step 179.9: 3-Bromo-1,1-diethoxy-propan-2-one

Copper (II) bromide (159 g, 711 mmol, 2.1 equiv) was added to amechanically stirred solution of pyruvic aldehyde dimethyl acetal (40 g,339 mmol) in EtOAc (1.5 L) at rt. The reaction mixture was heated toreflux, stirred for 3 h, cooled to rt, quenched by addition of asaturated aqueous solution of NaHCO₃ (500 mL), stirred for 30 min andfiltered through a pad of celite. The filtrate was extracted with EtOAcand the combined organic extracts were washed with H₂O and brine, dried(Na₂SO₄), filtered and concentrated. The residue was purified bydistillation to afford 22.4 g of the title compound as a yellow oil:ES-MS: 223/225 [M+H]⁺; bp: 80° C./40 mmbar.

Step 179.10: N-tert-Butoxycarbonylguanidine

Guanidine hydrochloride (175 g, 1833 mmol, 4 equiv) was added to asolution of NaOH (147 g, 3666 mmol, 8 equiv) in H₂O (360 mL),portionwise and keeping the internal temperature around 0° C.tert-Butoxycarbonyl anhydride (100 g, 458 mmol) in acetone (1.5 L) wasthen added over 2 h and the reaction mixture was allowed to warm to rtover 14 h. The acetone was removed under vacuum and the resultingaqueous mixture was extracted with EtOAc. The organic phase was washedwith H₂O and brine, dried (Na₂SO₄), filtered and concentrated to afford61.6 g of the title compound as a white solid: ES-MS: 160 [M+H]⁺.

Example 1808-(2,6-Dichloro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid(4-{[(2-dimethylamino-ethyl)-methyl-amino]-methyl}-1H-imidazol-2-yl)-amide

Sodium triacetoxyborohydride (168 mg, 0.794 mmol, 3 equiv) was added toa suspension of8-(2,6-dichloro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid(4-formyl-1H-imidazol-2-yl)-amide (125 mg, 0.265 mmol) (Example 179) andN,N,N′-trimethylethylenediamine (81 mg, 0.792 mmol, 3 equiv) in DCM (4mL) at rt, under an argon atmosphere. The reaction mixture was stirredfor 18 h at rt, diluted in DCM/H₂O and extracted with DCM. The organicphase was washed with H₂O and brine, dried (Na₂SO₄), filtered andconcentrated. The residue was purified by silica gel columnchromatography (DCM/MeOH/NH₃ ^(aq), 94:5:1) followed by trituration inEt₂O to afford 88 mg of the title compound as a yellow solid: ES-MS: 558[M+H]⁺; t_(R)=3.14 min (System 1); TLC: R_(f)=0.05 (DCM/MeOH/NH₃ ^(aq),94:5:1).

Example 1818-(2,6-Dichloro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid{4-[(2,2,2-trifluoro-ethylamino)-methyl]-1H-imidazol-2-yl}-amide

Sodium triacetoxyborohydride (101 mg, 0.476 mmol, 3 equiv) was added toa suspension of8-(2,6-dichloro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid(4-formyl-1H-imidazol-2-yl)-amide (75 mg, 0.159 mmol) andtrifluoroethylamine (15 μl, 0.188 mmol), 1.18 equiv) in DCM (3 mL) atrt, under an argon atmosphere. The reaction mixture was stirred for 18 hat rt, quenched by addition of H₂O and extracted with DCM. The organicphase was washed with a saturated aqueous solution of NaHCO₃, dried(Na₂SO₄), filtered and concentrated. The residue was purified by silicagel column chromatography (DCM/MeOH/NH₃ ^(aq), 98:1:1) followed bytrituration in Et₂O to afford 55 mg of the title compound as a yellowsolid: ES-MS: 555 [M+H]⁺; t_(R)=3.78 min (System 1); TLC: R_(f)=0.55(DCM/MeOH, 9:1).

Example 1828-(2,6-Dichloro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid{4-[(cyanomethyl-methyl-amino)-methyl]-1H-imidazol-2-yl}-amide

The title compound was prepared in analogy to the procedure described inExample 181 but using ethylaminoacetonitrile hydrochloride instead oftrifluoroethylamine. Title compound: ES-MS: 526/528 [M+H]⁺; t_(R)=3.88min (System 1); TLC: R_(f)=0.24 (DCM/MeOH, 9:1).

Example 1838-(2,6-Dichloro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid[4-(3-cyano-azetidin-1-ylmethyl)-1H-imidazol-2-yl]-amide

The title compound was prepared in analogy to the procedure described inExample 181 but using ethylaminoacetonitrile hydrochloride instead oftrifluoroethylamine. Title compound: ES-MS: 538/540 [M+H]⁺; t_(R)=3.49min (System 1); TLC: R_(f)=0.48 (DCM/MeOH, 9:1).

Example 1848-(2,6-Dichloro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid[4-(3,3-difluoro-azetidin-1-ylmethyl)-1H-imidazol-2-yl]-amide

The title compound was prepared in analogy to the procedure described inExample 180 but using 3,3-difluoroazetidine hydrochloride (1.2 equiv)instead of N,N,N′-trimethylethylenediamine and stirring the reactionmixture for 72 h at rt. Title compound: ES-MS: 549/551 [M+H]⁺;t_(R)=3.65 min (System 1); TLC: R_(f)=0.55 (DCM/MeOH/NH₃ ^(aq),91.5:7.5:1).

Example 1858-(2,6-Difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid(4-formyl-1H-imidazol-2-yl)-amide

A mixture of8-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid (200mg, 0.578 mmol) (Step 185.1),2-amino-4-diethoxymethyl-imidazole-1-carboxylic acid tert-butyl ester(198 mg, 0.693 mmol, 1.2 equiv) (Step 179.8), TBTU (223 mg, 0.693 mmol,1.2 equiv), DIEA (74.7 mg, 0.578 mmol) in DMF (4 mL) was stirred for 18h at rt. The reaction mixture was diluted in EtOAc/H₂O and extractedwith EtOAc. The organic phase was washed with H₂O and brine, dried(Na₂SO₄), filtered and concentrated. The resulting yellow foam (405 mg)was dissolved in acetone (5 mL) and H₂O (3 mL) and treated with PPTS (30mg). The reaction mixture was heated to 50° C., stirred for 2 h, allowedto cool to rt and diluted with EtOAc/H₂O. The resulting yellowprecipitate was collected by vacuum filtration and dried to provide 174mg of the title compound: ES-MS: 440 [M+H]⁺; t_(R)=3.89 min (System 1).

Step 185.1:8-(2,6-Difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid

A mixture of8-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acidethyl ester (885 mg, 2.37 mmol) (Step 185.2), a 2N aqueous solution ofLiOH (8 mL) and THF (8 mL) was stirred for 16 h at rt. THF was removedunder vacuum. The resulting mixture was diluted with Et₂O/H₂O. Theaqueous layer was separated and extracted with Et₂O. The aqueous layerwas acidified to pH 6 by addition of a 2N aqueous solution of HCl. Theresulting yellow precipitate was collected by vacuum filtration anddried to provide 701 mg of the title compound: ESI-MS: 347 [M+H]⁺;t_(R)=3.16 min (System 1)

Step 185.2:8-(2,6-Difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acidethyl ester

2,6-dichloro-1-fluoropyridinium tetrafluoroborate (13.9 g, 54.6 mmol,1.8 equiv) was added to a cold (−5° C.) solution of8-(3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid ethyl ester (Step185.3) (10.1 g, 29.9 mmol) in CH₃CN (100 mL). The reaction mixture wasallowed to warm to rt overnight, cooled to 5° C. and quenched byaddition of a saturated aqueous solution of NaHCO₃ (20 mL). The organicsolvent was removed in vacuo and the residual layer was diluted in EtOAcand a saturated aqueous solution of NaHCO₃. The aqueous phase wasseparated and extracted with EtOAc. The combined organic layers werewashed with H₂O and brine, dried (Na₂SO₄), filtered and concentrated.Several purifications by silica gel column chromatography (DCM/Hex/Et₂₀,1:3:6) provide 2.93 g of the title compound as a white solid. Titlecompound: ESI-MS: 375 [M+H]⁺; t_(R)=4.60 min (System 1); TLC: R_(f)=0.19(DCM/Hex/Et₂₀, 1:3:6).

Step 185.3: 8-(3,5-Dimethoxy-phenyl)-quinoxaline-5-carboxylic acid ethylester

A mixture of 8-(3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid(Step 179.2) (10 g), H₂SO₄ conc. (3 mL) and EtOH (500 mL) was stirred atreflux for 7 h, allowed to cool and concentrated. The residue wasdiluted in EtOAc and a saturated aqueous solution of NaHCO₃. The aqueousphase was separated and extracted with EtOAc. The combined organiclayers were washed with H₂O and brine, dried (Na₂SO₄), filtered andconcentrated to afford 10.1 g of the title compound as a beige solid.Title compound: ESI-MS: 339 [M−H]⁻; t_(R)=4.72 min (System 1).

Example 1868-(2,6-Difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid(4-methylaminomethyl-1H-imidazol-2-yl)-amide

Sodium triacetoxyborohydride (72.4 mg, 0.341 mmol, 1.5 equiv) was addedto a suspension of8-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid(4-formyl-1H-imidazol-2-yl)-amide (100 mg, 0.228 mmol) (Example 185) andmethylamine (40% wt in H₂O, 40 μL, 0.455 mmol, 2 equiv) in DCM (4 mL) atrt, under an argon atmosphere. The reaction mixture was stirred for 4 hat rt. After further addition of sodium triacetoxyborohydride (72.4 mg,0.341 mmol, 1.5 equiv), the reaction mixture was stirred for additional16 h at rt. Then, methylamine (50 μL) and sodium triacetoxyborohydride(150 mg) were added. The reaction mixture was stirred for 4 h at rt,diluted with EtOAc/saturated aqueous solution of NaHCO₃ and extractedwith DCM. The organic phase was dried (Na₂SO₄), filtered andconcentrated. The residue was purified by silica gel columnchromatography (DCM/MeOH/NH₃ ^(aq), 91.5:7.5:1) to afford 41 mg of thetitle compound as a yellow solid: ES-MS: 455 [M+H]⁺; t_(R) ⁼3.00 min(System 1); TLC: R_(f)=0.10 (DCM/MeOH/NH₃ ^(aq), 91.5:7.5:1).

Example 1878-(2,6-Difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid(4-N,N-dimethyl-N-oxidyl-aminomethyl-1H-imidazol-2-yl)-amide

A mixture of8-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid(4-dimethylaminomethyl-1H-imidazol-2-yl)-amide (30 mg, 0.64 mmol) (Step187.1) and mCPBA (20.1 g, 0.064 mmol) was stirred for 30 min at 5° C.,diluted with DCM/saturated aqueous solution of NaHCO₃ and extracted withDCM/MeOH (9:1, v/v). The organic phase was dried (Na₂SO₄), filtered andconcentrated. The residue was purified by silica gel columnchromatography (DCM/MeOH/NH₃ ^(aq), 89:10:1) to afford 20 mg of thetitle compound as a yellow solid: ES-MS: 485 [M+H]⁺; t_(R)=3.21 min(System 1); TLC: R_(f)=0.05 (DCM/MeOH/NH₃ ^(aq), 89:10:1).

Step 187.1:8-(2,6-Difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid(4-dimethylaminomethyl-1H-imidazol-2-yl)-amide

The title compound was prepared in analogy to the procedure described inExample 180 but using dimethylamine hydrochloride (1.5 equiv) instead ofN,N,N′-trimethylethylenediamine and8-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid(4-formyl-1H-imidazol-2-yl)-amide (Example 7). Title compound: ES-MS:469 [M+H]⁺; t_(R)=3.14 min (System 1); TLC: R_(f)=0.22 (DCM/MeOH/NH₃^(aq), 91.5:7.5:1).

¹H NMR data for selected examples are provided in the following table:

Example ¹H NMR Data (400 MHz, DMSO-d6) 81 δ(ppm): 2.11 (s, 6 H), 2.14(s, 3 H), 2.30-2.46 (m, 4 H), 3.49 (s, 2 H), 3.98 (s, 6 H), 7.05 (s, 1H), 7.80 (d, J = 8.4 Hz, 1 H), 7.93 (d, J = 7.8 Hz, 1 H), 8.29 (s, 1 H),8.35 (d, J = 8.2 Hz, 1 H), 8.76 (d, J = 7.4 Hz, 1 H), 9.06 (s, 1 H),9.19 (s, 1 H), 12.70 (s, 1 H) 92 δ(ppm): 0.96 (t, J = 7.23 Hz, 3 H),2.28 (q, J = 7.43 Hz, 2 H), 2.30-2.60 (m, 8 H), 3.47 (s, 2 H), 3.92 (s,6 H), 7.15 (t, J = 8.41 Hz, 1 H), 7.80 (dd, J = 8.60, 2.35 Hz, 1 H),8.11 (d, J = 7.82 Hz, 1 H), 8.29 (d, J = 1.56 Hz, 1 H), 8.35 (d, J =8.60 Hz, 1 H), 8.71 (d, J = 7.82 Hz, 1 H), 9.10 (d, J = 1.56 Hz, 1 H),9.20 (d, J = 1.96 Hz, 1 H), 12.59 (s, 1 H) 122 δ(ppm): 2.15 (s, 3 H),2.20-2.58 (m, 8 H), 2.59 (s, 3 H), 2.84 (s, 3 H), 3.47 (s, 2 H), 3.98(s, 6 H), 7.04 (s, 1 H), 7.75 (d, J = 7.82 Hz, 1 H), 7.79 (d, J = 8.60Hz, 1 H), 8.32 (s, 1 H), 8.35 (d, J = 8.60 Hz, 1 H), 8.70 (d, J = 7.82Hz, 1 H), 13.43 (s, 1 H) 127 δ(ppm): 2.14 (s, 6 H), 3.32 (s, 2 H), 3.92(s, 6 H), 6.67 (br s, 1 H), 7.15 (t, J = 8.41 Hz, 1 H), 8.10 (d, J =7.82 Hz, 1 H), 8.62 (d, J = 7.43 Hz, 1 H), 9.10 (s, 1 H), 9.18 (s, 1 H)135 δ(ppm): 2.38 (br s, 4 H), 3.31 (s, 2 H), 3.55 (br s, 4 H), 3.92 (s,6 H), 6.74 (br s, 1 H), 7.15 (t, J = 8.41 Hz, 1 H), 8.10 (d, J = 7.43Hz, 1 H), 8.64 (br. s., 1 H), 9.10 (s, 1 H), 9.19 (br s, 1 H), 11.77 (brs, 1 H), 12.68 (br s, 1 H) 141 δ(ppm): 2.12 (s, 3 H), 2.20-2.50 (m, 8H), 3.32 (s, 2 H), 3.92 (s, 6 H), 6.69 (br s, 1 H), 7.15 (t, J = 8.41Hz, 1 H), 8.10 (d, J = 7.43 Hz, 1 H), 8.63 (d, J = 7.04 Hz, 1 H), 9.10(s, 1 H), 9.19 (s, 1 H) 142 δ(ppm): 2.58 (br s, 2 H), 2.94 (s, 2 H),3.13 (br s, 2 H), 3.41 (br s, 2 H), 3.92 (s, 6 H), 6.79 (br s, 1 H),7.15 (t, J = 8.4 Hz, 1 H), 7.71 (br s, 1 H), 8.10 (d, J = 7.8 Hz, 1 H),8.63 (d, J = 5.5 Hz, 1 H), 9.10 (s, 1 H), 9.19 (br s, 1 H), 11.81 (br s,1 H), 12.68 (br s, 1 H) 145 δ(ppm): 0.96 (t, J = 7.0 Hz, 3 H), 1.90-2.70(m, 10 H), 3.47 (s, 2 H) 3.95 (br s, 6 H), 7.10 (d, J = 7.8 Hz, 1 H),7.80 (d, J = 8.2 Hz, 1 H), 8.02 (d, J = 7.8 Hz, 1 H), 8.28 (s, 1 H),8.34 (d, J = 8.6 Hz, 1 H), 8.73 (d, J = 7.4 Hz, 1 H), 9.07 (s, 1 H),9.19 (s, 1 H), 12.64 (s, 1 H) 152 δ(ppm): 2.70-3.20 (m, 8 H), 3.70 (s, 2H), 3.95 (d, J = 3.13 Hz, 6 H), 7.10 (d, J = 7.82 Hz, 1 H), 7.86 (d, J =8.60 Hz, 1 H), 8.02 (d, J = 7.43 Hz, 1 H), 8.25-8.48 (m, 2 H), 8.72 (d,J = 7.43 Hz, 1 H), 9.07 (s, 1 H), 9.19 (s, 1 H), 12.65 (s, 1 H) 155δ(ppm): 2.58 (br s, 2 H), 2.94 (s, 2 H), 3.13 (br s, 2 H), 3.42 (br s, 2H), 3.95 (s, 6 H), 6.79 (br s, 1 H), 7.10 (d, J = 7.8 Hz, 1 H), 7.70 (brs, 1 H), 8.02 (d, J = 7.4 Hz, 1 H,) 8.64 (br s, 1 H), 9.07 (s, 1 H),9.18 (s, 1 H), 11.81 (br s, 1 H), 12.71 (br s, 1 H) 157 δ(ppm): 1.00 (t,J = 7.2 Hz, 3 H), 2.13 (s, 3 H), 2.38 (q, J = 7.0 Hz, 2 H), 3.39 (br s,2 H), 3.92 (s, 6 H), 6.68 (br s, 1 H), 7.15 (t, J = 8.2 Hz, 1 H), 8.10(d, J = 7.8 Hz, 1 H), 8.63 (d, J = 7.4 Hz, 1 H), 9.10 (s, 1 H), 9.18 (s,1 H) 158 δ(ppm): 0.98 (t, J = 7.04 Hz, 6 H), 2.36-2.57 (m, 4 H), 3.46(br s, 2 H), 3.92 (s, 6 H), 6.68 (br s, 1 H), 7.15 (t, J = 8.21 Hz, 1H), 8.09 (d, J = 7.43 Hz, 1 H), 8.62 (d, J = 7.43 Hz, 1 H), 9.09 (s, 1H), 9.18 (s, 1 H) 177 ¹H NMR (600 MHz) δ(ppm): 2.20 (br s, 6 H), 3.45(br s, 2 H), 3.99 (s, 6 H), 6.75 (br s, 1 H), 7.19 (d, J = 7.9 Hz, 1 H),7.75 (dd, J = 8.3, 4.0 Hz, 1 H), 7.82 (d, J = 7.7 Hz, 1 H), 8.03 (d, J =8.5 Hz, 1 H), 8.80 (br s, 1 H), 9.22 (br s, 1 H), 11.77 (br s, 1 H),13.88 (br s, 1 H) 178 ¹H NMR (600 Mz) δ(ppm): 2.16 (s, 3 H), 2.33-2.49(m, 8 H), 3.34 (br s, 2 H), 3.99 (d, J = 5.0 Hz, 6 H), 6.74 (br s, 1 H),7.19 (d, J = 7.9 Hz, 1 H), 7.75 (dd, J = 8.5, 4.2 Hz, 1 H), 7.82 (d, J =7.5 Hz, 1 H), 8.03 (d, J = 8.3 Hz, 1 H), 8.80 (d, J = 7.7 Hz, 1 H), 9.23(br s, 1 H), 11.76 (br s, 1 H), 13.86 (br s, 1 H) 180 δ(ppm): 2.07-2.23(m, 9 H), 2.32-2.39 (m, 2 H), 2.39-2.46 (m, 2 H), 3.42 (br s, 2 H), 3.98(s, 6 H), 6.67 (br s, 1 H), 7.06 (s, 1 H), 7.92 (d, J = 7.43 Hz, 1 H),8.67 (d, J = 7.82 Hz, 1 H), 9.05 (d, J = 1.56 Hz, 1 H), 9.16 (d, J =1.56 Hz, 1 H) 183 δ(ppm): 3.30-4.20 (m, 13 H), 6.72 (br s, 1 H), 7.06(s, 1 H), 7.92 (d, J = 7.8 Hz, 1 H), 8.67 (d, J = 6.6 Hz, 1 H), 9.05 (s,1 H), 9.16 (s, 1 H), 11.77 (br s, 1 H), 12.73 (br s, 1 H) 186 δ(ppm):2.25 (s, 3 H), 3.52 (br s, 2 H), 3.92 (s, 6 H), 6.65 (br s, 1 H), 7.15(t, J = 8.21 Hz, 1 H), 8.10 (d, J = 7.43 Hz, 1 H), 8.63 (d, J = 7.43 Hz,1 H), 9.09 (s, 1 H), 9.17 (s, 1 H) br: broad; s: singlet; d: doublet; t:triplet; q: quartet; Hz: Hertz; ppm: part per million

The ¹H-NMR spectra were measured on either a Varian Mercury 400spectrometer or a Bruker Avance 600 spectrometer.

Example 188 Pharmaceutical Formulations Example 188.1 Soft Capsules

5000 soft gelatin capsules, each comprising as active ingredient 0.05 gof any one of the compounds of formula (I) mentioned in any one of thepreceding Examples are prepared as follows: 250 g pulverized activeingredient is suspended in 2 liters Lauroglykol*(propylene glycollaurate, Gattefossé S.A., Saint Priest, France) and ground in a wetpulverizer to produce a particle size of about 1 to 3 μm. 0.419 gportions of the mixture are then introduced into soft gelatin capsulesusing a capsule-filling machine.

Example 188.2 Tablets

Tablets, comprising, as active ingredient 100 mg of any one of thecompounds of formula (I) mentioned in any one of the preceding Examplesare prepared with the following composition according to standardprocedures.

compound (I) 100 mg crystalline lactose 240 mg Avicel 80 mg PVPPXL 20 mgAerosil 2 mg magnesium stearate 5 mg

The active ingredient is mixed with the carrier materials and compressedby means of a tabletting machine (Korsch EKO, stamp diameter 10 mm).Avicel® is microcrystalline cellulose (FMC, Philadelphia, USA). PVPPXLis polyvinylpolypyrrolidone, cross-linked (BASF, Germany). Aerosil® issilicon dioxide (Degussa, Germany).

Example 189 Protein Kinase Activities Assays

Selected compounds of formula (I) are assayed to measure their capacityto inhibit protein kinases as described herein.

Example 189.1 Protein Kinase Activities Measured by a Radiometric Assay

generic assay set-up: Enzyme activities were measured by mixing 10 μL ofa 3-fold concentrated compound solution or control with 10 μL of thecorresponding substrate mixture (peptidic substrate, ATP and [γ³³F]ATP).The reactions were initiated by addition of 10 μL of a 3-foldconcentrated solution of the respective enzyme in assay buffer. Thefinal concentrations of the assay components were as following:(FGFR-3-K650E) 10 ng of GST-FGR-3-K650E, 20 mM Tris-HCl, pH 7.5, 3 mMMnCl₂, 3 mM MgCl₂, 1 mM DTT, 250 μg/mL PEG 20′000, 2 μg/mL poly(EY) 4:1,1% DMSO and 0.5 μM ATP (γ-[³³P]-ATP 0.1 μCi), (KDR) 15 ng of GST-KDR, 20mM Tris-HCl, pH 7.5, 1.0 mM MnCl₂, 10 mM MgCl₂, 1 mM DTT, 10 μM Na₃VO₄,250 μg/mL PEG 20′000, 8.0 μg/mL poly(Glu, Tyr) 4:1, 1% DMSO and 8.0 μMATP (γ-[³³P]-ATP 0.1 μCi), (PDGFR-beta) 30 ng of GST-Xa-PDGF-beta, 20 mMTris-HCl, pH 7.5, 10 mM MnCl₂, 3.0 mM MgCl₂, 1 mM DTT, 10 μM Na₃VO₄, 250μg/mL PEG 20′000, 3.0 μg/mL poly(Glu, Tyr) 4:1, 1% DMSO and 1.0 μM ATP(γ-[³³P]-ATP 0.1 μCi), (RET) 15 ng of GST-Ret, 20 mM Tris-HCl, pH 7.5,1.0 mM MnCl₂, 10 mM MgCl₂, 1 mM DTT, 3.0 μg/mL poly(Glu, Tyr) 4:1, 1%DMSO and 2.0 μM ATP (μ-[³³P]-ATP 0.1 μCi.

Filter binding (FB) method: FB assays were carried out in 96-well platesat room temperature for 10 min in a finial volume of 30 μL including thecomponents as indicated in section above. The enzymatic reactions werestopped by the addition of 20 μL of 125 mM EDTA and the incorporation of³³P into the poly-peptidic substrates were quantified as following: 30μL of the stopped reaction mixture were transferred onto Immobilon-PVDFmembranes previously soaked for 5 min with methanol, rinsed with water,soaked for 5 min with 0.5% H₃PO₄ and mounted on vacuum manifold withdisconnected vacuum source. After spotting, vacuum was connected andeach well rinsed with 200 μL 0.5% H₃PO₄. Free membranes were removed andwashed 4 times on a shaker with 1% H₃PO₄ and once with ethanol.Membranes were dried and overlaid with addition of 10 μL/well of ascintillation fluid. The plates were eventually sealed and counted in amicroplate scintillation counter. IC₅₀ values were calculated by linearregression analysis of the percentage inhibition of the compound.

Example 189.2 Protein Kinase Activities Measured by the LanthaScreenTR-FRET Method

generic assay set-up: The assay has been run at room temperature on aliquid handling robot. To the assay plates containing 50 mL compound orcontrol solutions, 4.5 μL of solution A (50 mM Tris-HCl pH7.4, 2.0mMDTT, 0.05% Tween20, 0.02 mM Na₃VO₄) including a generic concentrationof 2.0 μM ATP was added per well, followed by 4.5 μL of solution B (0.5%BSA) including a generic concentration of 50 nM poly(EAY) to give 9.05μL of a reaction volume with final concentrations of 2.0 μM ATP, 50 nMpoly(EAY), 25 mM Tris-HCl pH7.4, 1.0 mM DTT, 0.025% Tween20, 0.01 mMNa₃VO₄, 0.025% BSA as well as specific concentration of the respectiveenzyme and individual concentrations of divalent cations: (FGFR-3-K650E)0.2 nM GST-FGR-3-K650E, 3.0 mM MgCl₂, (KIT) 36.6 nM GST-KIT, 10 mMMnCl₂, (RET) 0.11 nM GST-Xa-RET, 1.0 mM MnCl₂, 10 mM MgCl₂, (LCK) 3.3 nMHis-LCK, 10 mM MnCl₂. (KDR) 0.38 nM GST-KDR, 10 mM MgCl₂, 1.0 mM MnCl₂,(PDGFaV561D) 4.4 nM GST-PDGFRaV561 D, 10 mM MnCl₂. After 1 hour ofincubation the kinase reactions have been stopped by the addition of 4.5μL of stop solution D (48 mM EDTA, 0.08% CH₃COONa, 0.04% NP-40)immediately followed by 4.5 μL of solution A including the Tb-labeledP-20 antibody to detect phosphorylated poly(EAY) by TR-FRET(Time-Resolved Fluorescence Resonance Energy Transfer). The totaldetection volume of 18.05 μL included the following components: 1.0 mMATP, 25 nM poly(EAY), half the concentrations of individual enzymes anddivalent cations as indicated above and 12 mM EDTA, 0.43 μg/mL Tb-PY20antibody (2.85 nM), 25 mM Tris-HCl pH7.4, 1.0 mMDTT, 0.025% Tween20,0.01 mM Na₃VO₄, 0.01 mM Na₃VO₄, 0.025%, 0.02% CH₃COONa, 0.01% NP-40).After an incubation time of 45 min in the dark, the plates weretransferred into a fluorescence reader for counting. The effect ofcompound on the enzymatic activity was obtained from the linear progresscurves and determined from one reading (end point measurement).

Example 189.3 Protein Kinase Activities Measured by the MicrofluidicCaliper Method (I)

generic assay set-up: The assay was prepared and incubated on a liquidhandling robot system using 384 well plates. To the assay platescontaining 50mL compound or control solutions, 4.5 μL of solution Aconsisting of the peptide substrate and ATP in assay buffer were added.The reactions were initiated by adding 4.5 μL of solution B consistingof the respective kinase in assay buffer. The reactions were incubatedfor 1 hour at 30° C. in a final reaction volume of 9.05 μL. Based on ageneric assay buffer (50 mM HEPES pH7.5, 1 mM DTT, 0.02% Tween20, 0.02%BSA), the following components were added:

(cAbl) 16 nM His-cAbl, 5 μM peptide substrate(FITC-Ahx-EAIYAAPFAKKK-CONH2), 10 mM MgCl₂, 10 μM ATP. After incubation,the kinase reactions were stopped by the addition of 16 μL of stopsolution (100 mM HEPES, 5% DMSO, 0.1% Coating reagent, 10 mM EDTA,0.015% Brij 35). Subsequently, the assay plates were transferred to aCaliper LabChip3000 reader and the unphosphorylated substrate and thephosphorylated product were separated and quantitated in a microfluidicchip. From these data the turnover of the kinase reactions and theeffects of the compounds were calculated.

Example 189.4 Protein Kinase Activities Measured by the MicrofluidicCaliper Method (II)

generic assay set-up: The assay was prepared and incubated on a liquidhandling robot system using 384 well plates. To the assay platescontaining 50mL compound or control solutions, 4.5 μL of solution Aconsisting of the peptide substrate and ATP in assay buffer were added.The reactions were initiated by adding 4.5 μL of solution B consistingof the respective kinase in assay buffer. The reactions were incubatedfor 1 hour at 30° C. in a final reaction volume of 9.05 μL. Based on ageneric assay buffer (50 mM HEPES pH7.5, 1 mM DTT, 0.02% Tween20, 0.02%BSA), the following components were added:

(cAbl-T315I) 2.4 nM His-cAbl-T3151, 5 μM peptide substrate(FITC-Ahx-EAIYAAPFAKKK-CONH2), 10 mM MgCl₂, 10 μM ATP. After incubation,the kinase reactions were stopped by the addition of 16 μL of stopsolution (100 mM HEPES, 5% DMSO, 0.1% Coating reagent, 10 mM EDTA,0.015% Brij 35). Subsequently, the assay plates were transferred to aCaliper LabChip3000 reader and the unphosphorylated substrate and thephosphorylated product were separated and quantitated in a microfluidicchip. From these data the turnover of the kinase reactions and theeffects of the compounds were calculated.

Compounds of formula (I) are assayed to measure their capacity toinhibit FGFR3 kinase as described above.

Results are provided in the following table:

rating example no. Excellent 1, 5, 6, 8-14, 18-23, 25-27, 31, 33, 34,37, (IC50 < 0.1 μM) 39-43, 81, 88, 89, 92-95, 100-103, 105-109, 118-120,122-138, 140, 141, 143-154, 159, 161, 164, 167, 172, 174-178 Good 38,85, 90, 91, 104, 111-114, 139, 162, 165, (0.1 < IC50 < 0.5 μM) 168, 169,173 Moderate 2-4, 7, 17, 24, 45-51, 56-62, 65, 67-70, 72, (0.5 μM < IC50< 50 μM) 75-80, 82, 83, 86, 87, 97-99, 115, 117, 121, 160, 163, 171

Selected results for specific compounds are provided in the followingtable:

Example FGFR3 IC₅₀ (nM) 2 530* 3 >10000*    4 1300*  6  74* 10  58* 11 31* 17 >10000*    20  16* 22  10* 24 530* 25  41* 31  22* 34  54* 38270  43 87 56 1200*  58 700* 62 8100*  69 >10000*    77 >10000     82605  83 945  85 210  86 2550  91 485  93  7* 95 42 97 875  98 1050 99 >10000     106 20 112 139  122 14 124 10 127 16 135 11 136 11 139265  143 44 144  7 152 32 153 11 154  9 155 12 167 99 172 70 173 245 174 16 175  9 176 51 177 10 IC₅₀ values are the average IC₅₀ values of 2independent measurements. *Single value.

Further, selected compounds of formula (I) are assayed to measure theircapacity to inhibit other kinases, such as KDR, cKIT, PDGF-R, LCK, cABL,RET as described above. Results are provided in the following table:

Enzyme KDR cKIT PDGF-R LCK cABL RET IC50 (μM) 0.003- 0.240- 0.100-0.170- 0.010- 0.390- range 50 50 50 50 50 50

1. A method for the treatment of a protein tyrosine kinase mediateddisease, comprising the step of administering to a subject in needthereof a therapeutically effective amount of a compound selected fromthe group consisting of:8-(2,6-Dichloro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid(4-dimethylaminomethyl-1H-imidazol-2-yl)-amide,8-(2,6-Difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid(4-dimethylaminomethyl-1H-imidazol-2-yl)-amide,8-(2,6-Dichloro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid[5-(4-ethyl-piperazin-1-ylmethyl)-pyridin-2-yl]-amide,8-(2,6-Difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid[5-(4-ethyl-piperazin-1-ylmethyl)-pyridin-2-yl]-amide,8-(2-Chloro-6-fluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid[5-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-yl]-amide, and8-(2-Chloro-6-fluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid(5-piperazin-1-ylmethyl-pyridin-2-yl)-amide; or a pharmaceuticallyacceptable salt thereof.
 2. The method according to claim 1 wherein theprotein tyrosine kinase mediated disease is a FGFR kinase mediateddisease.
 3. The method according to claim 2 wherein the FGFR kinasemediated disease is cancer.
 4. The method according to claim 3 whereinin the cancer is selected from the group consisting of cancer of thebladder, cancer of the cervix, oral squamous cell carcinoma, multiplemyeloma, breast cancer, endometrial cancer, hepatocellular cancer, a EMSmyeloproliferative disorder, lymphoma, glioblastoma, gastric carcinoma,pancreatic carcinoma, prostate carcinoma and a pituitary tumor.
 5. Themethod according to claim 4 wherein the compound is8-(2,6-Dichloro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid(4-dimethylaminomethyl-1H-imidazol-2-yl)-amide of formula

or a pharmaceutically acceptable salt thereof.
 6. The method accordingto claim 4 wherein the compound is8-(2,6-Difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid(4-dimethylaminomethyl-1H-imidazol-2-yl)-amide of formula

or a pharmaceutically acceptable salt thereof.
 7. The method accordingto claim 4 wherein the compound is8-(2,6-Dichloro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid[5-(4-ethyl-piperazin-1-ylmethyl)-pyridin-2-yl]-amide of formula

or a pharmaceutically acceptable salt thereof.
 8. The method accordingto claim 4 wherein the compound is8-(2,6-Difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid[5-(4-ethyl-piperazin-1-ylmethyl)-pyridin-2-yl]-amide of formula

or a pharmaceutically acceptable salt thereof.
 9. The method accordingto claim 4 wherein the compound is8-(2-Chloro-6-fluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid[5-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-yl]-amide of formula

or a pharmaceutically acceptable salt thereof.
 10. The method accordingto claim 4 wherein the compound is8-(2-Chloro-6-fluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid(5-piperazin-1-ylmethyl-pyridin-2-yl)-amide of formula

or a pharmaceutically acceptable salt thereof.